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Drug likeness  Properties

 Introduction
 Properties Are of Interest in Discovery
 Drug discovery
 Solubility
 Lipinski & Veber rules
 Applications of rules
 Property profiling
 Discovery Inefficiencies
Contents

 Drug-like is defined as those compounds that have
sufficiently acceptable ADME properties and sufficiently
acceptable toxicity properties to survive through the
completion of human Phase I clinical trial
 Drug-like properties confer good ADME/Tox
characteristics to a compound.
 Medicinal chemists control properties through structure
modification.
 Biologists use properties to optimize bioassays and
interpret biological experiments.
Introduction

Drug-like Properties Are an Integral Part of Drug
Discovery
The structure determines the compound’s properties.
 When the structural properties interact with the physical
environment, they cause physicochemical properties (e.g.,
solubility).
 When the structural properties interact with proteins,
they cause biochemical properties (e.g., metabolism).
 At the highest level, when the physicochemical and
biochemical properties interact with living systems they
cause PK and toxicity.
 Medicinal chemists control the PK and toxicity properties
of the compound by modifying the structure.
Drug-like Properties Are an Integral Part of Drug
Discovery
 Properties of interest to discovery scientists include the
following:
Many Properties Are of Interest in Discovery
Structural properties
Hydrogen bonding
Polar surface area
Lipophilicity
Shape
Molecular weight
Reactivity
pKa
Physicochemical properties
Solubility
Permeability
Chemical stability
 Biochemical properties
Metabolism (phases I and II)
Protein and tissue binding
Transport (uptake, efflux)
 Pharmacokinetics (PK) and toxicity
Clearance
Half-life
Bioavailability
Drug–drug interaction
LD50
Conti..

 Before exploring how properties affect drug candidates, it is
useful to briefly review the process of drug discovery and
development.
Introduction to the Drug Discovery and Development
Process
Overview of drug research and development stages and their major activities.

Stages of drug discovery, primary goals, and major activities.
 Many negative effects can occur for low-solubility
compounds, including the following:
 Poor absorption and bioavailability after oral dosing
 Insufficient solubility for IV dosing
 Artificially low activity values from bioassays
 Erratic assay results (biological and property methods)
 Development challenges (expensive formulations and
increased development time)
 Burden shifted to patient (frequent high-dose
administrations)
Solubility
 Solubility is the maximum dissolved concentration under
given solution conditions.
 Solubility is a determinant of intestinal absorption and oral
bioavailability.
 Increased by adding ionizable groups or reducing Log P
and MW.
 Salt forms increase dissolution rate.
Solubility
 Solubility Varies with Structure and Physical Conditions
Solubility is determined by many factors:
 Compound structure
 Physical state of compound that is introduced into solution
Solid: Amorphous, crystalline, polymorphic form
Liquid: Predissolved in solvent (e.g., dimethylsulfoxide [DMSO])
 Composition and physical conditions of solvent(s)
Types of solvents
Amount (%) of co-solvents
Solution components (e.g., salts, ions, proteins, lipids, surfactants)
pH
Temperature
Solubility Fundamentals
 Methods of measurement
Equilibration time
Separation techniques (e.g., filter, centrifuge)
Detection (e.g., ultraviolet, mass spectrometry, turbidity)
 Structural Properties Affect Solubility
 Solubility is affected by physicochemical properties, which can
be estimated using in vitro assays or software calculations.
 Lipophilicity: Determined by van der Waals, dipolar, hydrogen
bonds, ionic interactions
 Size: Molecular weight, shape
 pKa: Determined by functional group ionizability
 Crystal lattice energy: Determined by crystal stacking,
melting point
Conti..
Effects of Solubility
Solubility, permeability, and metabolic stability affect oral absorption and
bioavailability following oral dosing.
Example
Effect of solubility on oral bioavailability.
 The early lead compound L-685,434 had good
potency in vitro in both enzyme and cell-based
assays but was completely inactive in vivo after oral
dosing due to poor solubility.
 The compound was modified by introducing
ionizable centers into the molecule to increase
solubility.
 The modified compound (indinavir) is much more
soluble, maintains good potency, and has oral
bioavailability of 60% in human.
<10 μg/mL - Low solubility
10–60 μg/mL - Moderate solubility
>60 μg/mL - High solubility
In rating the solubility of compounds for discovery
project teams, the following solubility classification
ranges are suggested for medicinal chemists:
 It divides compounds into four classes based on solubility
and permeability
The Biopharmaceutics Classification System (BCS)
 Class I is high solubility and high permeability. This is
an ideal class for oral absorption.
 Class II is low solubility and high permeability.
Formulation typically is used to enhance solubility of
compounds in this class.
 Class III is high solubility but low permeability. Pro-
drug strategies typically are used for these compounds.
 Class IV is low solubility and low permeability.
Development of this class of compounds can be risky and
costly. No in vitro/in vivo correlations are expected.
Molecular Properties for Solubility and Permeability
Effects of structural properties on solubility and permeability.
Changing one property can affect several others.
 The figure shows how structural features that enhance solubility
often reduce permeability.
 For example, increasing charge, ionization, or hydrogen bonding
capacity will increase solubility but will decrease permeability.
 Increasing lipophilicity and size to some extent will increase
permeability but will decrease solubility.
 Medicinal chemists must balance the different structural features
to find a balance between solubility and permeability
for the clinical candidate in order to achieve optimal
absorption.
Structure Modification Strategies to Improve Solubility
Structure Modifications Strategies for Solubility Improvement
Add Ionizable Groups
 Addition of ionizable groups is commonly used for enhancing solubility.
 It is one of the most effective structural modifications to increase solubility.
 Typically, a basic amine or a carboxylic acid is introduced to the structure.
 Compounds with an ionizable functional group will be charged in pH buffers
and have increased solubility.
 One example is solubility enhancement of artemisinin, which is an antimalarial
agent.
 The sodium salt of a carboxylic acid analog achieved higher solubility,
but, in this case, the compound was unstable.
 Ultimately, the amine analogs attained better solubility and stability and were
active after oral dosing.
Add Hydrogen Bonding
• Introducing hydrogen bond donors and acceptors, such as OH and NH2,
can enhance aqueous solubility.
• Two anti-AIDS agents are shown.
• The first compound has poor aqueous solubility and poor oral
bioavailability, which limited its further development.
• Introducing a hydroxyl group into the molecule increased solubility and
oral bioavailability.
Reduce Log P
 Several protease inhibitors are shown Reducing Log P increased solubility
and led to higher systemic exposure, as indicated by enhanced maximum
concentrations in the blood, Cmax.
 Reducing Log P and increasing solubility enhances the in vivo exposure.
Add Polar Group
 Water solubility usually increases with the addition of a polar group.
 A series of epoxide hydrolase inhibitors.
 Solubility increased with the introduction of the ester group (more polar) and
carboxylic acid group (more polar and ionizable).
Reduce Molecular Weight
 Reduction in molecular weight is another useful approach for increasing
solubility.
 An example of CDK2 inhibitors.
 The lower molecular weight increased solubility and metabolic stability,
while maintaining in vitro activity.
 In vivo potency was improved because of the increased solubility and
stability.
Out-of-Plane Substitution
 Out-of-plane substitutions are illustrated in Figure.
 Addition of the ethyl group shifts the planarity of the molecule, resulting
in a disruption of the crystal packing to form a higher-energy crystal that is
more soluble.
Construct a Prodrug
 Charged or polar groups can be added to make prodrugs with increased
aqueous solubility.
 In figure shows fosphenytoin, which is a prodrug of phenytoin.
 The phosphate group greatly increases the solubility, making it much easier
to formulate for clinical dosing.
 Enzymatic hydrolysis in the intestine releases phenytoin for absorption.
Bioavailability (F)
• One of the most commonly used PK parameters is bioavailability (F).
• It is the fraction of the dose that reaches systemic circulation unchanged.
• Less than 100% bioavailability typically results from incomplete
intestinal absorption or first-pass metabolism.
• Secondary causes include enzymatic or pH-induced decomposition in the
intestine or blood.
Bioavailability is calculated from the expression:
Metabolic Stability
• Metabolism is the enzymatic modification of compounds to increase
clearance.
• It is a determinant of oral bioavailability, clearance, and half-life in vivo.
• Metabolism occurs predominantly in the liver, and some may occur in the
intestine.
• Metabolic stability is increased by structure modifications that block or
sterically interfere with metabolic sites or withdraw electrons.
Scheme for in vitro assessment of diverse stability challenges during drug discovery.
Drug stability can be broadly divided into two main areas:
stability after administration
shelf-life
Stability after administration
A drug will only be effective if, after administration, it is stable enough to
reach its target site in sufficient concentration to bring about the desired
effect.
However, as soon as a drug is administered the body starts to remove it by
metabolism.
Consequently, for a drug to be effective it must be stable long
enough after administration for sufficient quantities of it to reach its target
site. In other words, it must not be metabolised too quickly in the
circulatory system. Three strategies are commonly used for improving a
drug’s in situ stability, namely:
• Modifying its structure;
• Administering the drug as a more stable prodrug
• Using a suitable dosage form
Shelf-life
 Shelf-life is the time taken for a drug’s pharmacological activity to
decline to an unacceptable level.
 This level depends on the individual drug and so there is no universal
Specification.
 However, 10 per cent decomposition is often taken as an acceptable limit
provided that the decomposition products are not toxic.
Metabolic Stability Effects
 Metabolic stability affects pharmacokinetics (PK), as shown in Figure.
 Metabolic stability has an inverse relationship with clearance (Cl).
 A decrease in metabolic stability leads to an increase in clearance.
 Cl and volume of distribution (Vd) directly affect the PK half-life (t½ =
0693×Vd/Cl), which determines how often the dose must be administered.
Effects of metabolic stability on pharmacokinetics.

 Once a target and a testing system have been chosen,
the next stage is to find a lead compound—a
compound which shows the desired
pharmacological activity.
 The level of activity may not be very great and there
may be undesirable side effects, but the lead
compound provides a start for the drug design and
development process.
Finding a lead compound
 For example the antidiabetic agent tolbutamide, which was developed from a
sulfonamide structure.
 Most sulfonamides are used as antibacterial agents, but some proved
unsatisfactory since they led to convulsions brought on by hypoglycaemia
(low glucose levels in the blood).
 Structural alterations were made to eliminate the antibacterial activity and to
enhance the hypoglycaemic activity and this led to tolbutamide.
Tolbutamide.
 Analog is a compound having a structure similar to that
of another compound, but differing from it in respect of
certain component.
 In drug discovery either a large series of structural
analogs of an initial lead compound are created and
tested as part of a structure-activity relationship study or
a database is screened for structural analogs of a lead
compound.
Analog
Lipinski Rules
 It is important to keep in mind the intended purpose of the rule of 5.
 The article states: Poor absorption or permeation is more likely when:
1. There are more than 5 hydrogen bond donors (expressed as
the sum of all OH and NH groups)
2. MWt greater than 500
3. logP greater than 5
4. There are more than 10 hydrogen bond acceptors (expressed as the sum of all
Ns and Os)
5. Substrates for biological transporters are exceptions to this rule
THE RULES WERE SET AT THE 90th PERCENTILE OF THE COMPOUND SET
 This means that 90% of the compounds that had sufficient absorption after oral
dosing had molecular property values within the Lipinski Rules
 Compounds that approach or exceed these values have a higher risk of poor
absorption after oral dosing
The rules are based on a strong physicochemical rationale
 Hydrogen bonds increase solubility in water and must be broken in order for a
compound to permeate the lipid bilayer membrane
 Thus increasing the number of hydrogen bonds reduces partitioning from the
aqueous phase into the lipid bilayer membrane for permeation by passive
diffusion
 Increasing logP decreases aqueous solubility which reduces absorption
 Membrane transporters can either enhance or reduce compound
absorption by either active uptake transport or efflux respectively
 This means that transporters can have a strong impact on increasing or
decreasing absorption
THE LIPINSKI RULES
• are widely used as a filter and measurement of the drug-likeness of a series
of molecules.
• They are used to such an extent that they almost ‘copyright’ the field of
drug- likeness compound scoring.
• However, other experiments have also been carried out in this area….
VEBER RULES
 The results of an experiment performed by Veber et al.* examining
the oral bioavailability of potential drug candidates in the rat let to
the conclusion that other parameters existed for the description of
drug likeness than the Lipinski rules.
 The main parameter taken into account during this experiment was
the number of rotatable bonds – as an indication of molecular
flexibility.
 Veber’s experiments indicated that the main factor influencing the
possibility of uptake by the lumen is not molecular weight but, in fact the
number of rotatable bonds.
 This could be explained by the entropic cost of presenting an acceptable
drug surface area to hydrophobic surface of the membrane in the sense that
a compact molecule is easier to absorb than extended one.
 They therefore suggest the following filter for drug-likeness:
Rotatable bonds < 12
Polar surface area < 140
 Also, Veber et al. (2002) therefore raise the issue of molecular weight
being a proper descriptor for absorption measurement as molecular
weight might just be positively correlated with more precise properties
like the rotatable bonds count, polar surface area and hydrogen bonds
count.
 The Veber et al. experiments referred to above underline the difficulties
met with when trying to make generalizing rules for complex systems.
CORRESPONDENCE BETWEEN MOLECULAR WEIGHT, THE
NUMBER OF ROTATABLE BONDS AND THE DEGREE OF
BIOAVAILABILITY IN THE RAT
Application of Rules for Compound Assessment
Rules are typically used for the following purposes:
• Anticipating the drug-like properties of potential compounds when planning
synthesis
• Using the drug-like properties of “hits” from HTS as one of the selection
criteria
• Evaluating the drug-like properties of compounds being considered for
purchase from a compound vendor
Example of counting and calculations for the Lipinski and Veber rules for
doxorubicin, which has an oral bioavailability of approximately 5%.
Property Profiling in Discovery
 Property profiling should be rapid and use relevant assay conditions.
 Use a diverse set of assays that have high impact for the organization.
 Property assays consume resources and influence projects, so assays
should be carefully implemented.
 Evaluate the cost versus benefit of assays.
Property Data Should be Rapidly Available
• In order for property data to be relevant for discovery, they need to be
reported to project teams rapidly.
• This allows decisions to be made rapidly so that aggressive discovery
time lines can be met.
• Faster data allow more iterations of trying new ideas to optimize the
compounds, thus increasing the success rate.
• A general guide is to provide data in a few days to 2 weeks, the same
time frame as biological data.
Use Relevant Assay Conditions
• The conditions of property assays need to be relevant to the environment
faced by the compound.
• Variables, such as concentration, pH, matrix components in solution, and
biological tissue extracts, must be controlled and designed to be reflective
of the barriers faced by the compound.
Evaluate the Cost-to-Benefit Ratio for Assays
• In any discovery organization there are always tradeoffs on the allocation
of resources.
• Thus, it is important to decide which properties are of greatest importance
to the organization.
• The properties that have the greatest impact on the projects and goals of
the organization should prevail.
• Assays should not be put in place because other organizations have them
but should be decided based on what the organization considers to be the
critical issues.
Choose an Ensemble of Key Properties to Evaluate
Each organization must select the properties they are most interested in
monitoring. For example,
Use Well-Developed Assays
• Data used for decision-making should be generated using assays that have
been well developed.
• The assay conditions can greatly affect the results.
Poor Drug Properties Also Cause Discovery Inefficiencies
• Once late-discovery biopharmaceutical assessment was in place and an
attrition burden was lifted from development, another discovery need was
revealed.
• Candidates that were failing in late discovery because of poor properties
still caused a great burden on drug discovery.
• Failure late in discovery meant that the project to discover a new drug had
lost valuable time and resources on the failed candidate and had to start
over.
Marginal Drug Properties Cause Inefficiencies During Development
• Although the rate of outright candidate failure in development has decreased
due to early termination of candidates with inadequate properties, candidates
with marginal properties still progress into development.
• Even though they might not fail in development, they impose significant
inefficiencies on development by increasing development costs and
prolonging development time lines.
Following are examples of how poor drug properties can reduce the
quality of drug discovery biological research:
• Low or inconsistent bioactivity responses for in vitro bioassays can be due to
precipitation, owing to low solubility of the compound in the bioassay medium
or in dilutions prior to the assay.
• Low activity in bioassays may be due to chemical instability of the compound
in the test matrix.
• An unexpectedly high drop in activity can result when transitioning from
enzyme or receptor activity assays to cell-based assays. This can be due to
poor permeability of the compounds through the cell membrane, which must
be penetrated for the compound to reach intracellular targets.
• Compounds may be unstable or insoluble in the DMSO solutions that are
stored in microtiter plates and experience freeze–thaw cycles, or they may be
exposed to various physicochemical conditions in the laboratory.
• Poor efficacy of a central nervous system (CNS) drug in vivo may be due to
poor penetration of the blood–brain barrier.
• Poor efficacy in vivo may be due to low concentrations in the plasma and
target tissue because of poor PK, low bioavailability, or instability in the
blood.
WHAT IS A FUNCTIONAL GROUP?
Functional groups provide specific properties and behaviors that allow drug
molecules to exert their desired pharmacodynamic and pharmacokinetic
effects.
For a given drug molecule they play a significant role in the:
• Overall water/lipid solubility
• Route of administration
• Ability to interact with specific biological targets
• Mechanism of action
• Route of metabolism and elimination
• Duration of action
• Suitability for a specific therapeutic situation
• Tendency to cause adverse effects or drug interactions
• When examining drug molecules, there are three overriding concepts that you
should always consider.
• First, every atom within the structure of a drug molecule is part of a specific
functional group.
• example of this concept by using the nonsteroidal anti-inflammatory agent,
indomethacin.
CHEMICAL PROPERTIES OF FUNCTIONAL GROUPS
 There are three major chemical properties that need to be considered for every
functional group.
 Each functional group has an electronic effect, a solubility effect, and a steric
effect that needs to be considered when evaluating the overall
pharmacodynamic and pharmacokinetic properties of any given drug molecule.
 Prior to proceeding, there are two key points to keep in mind.
 First of all, the addition of a single functional group to a given molecule will
affect the overall electronics, solubility, and steric dimensions of that molecule.
 It is impossible for a functional group to alter only one of these properties.
 As an example, consider a drug molecule that contains an unsubstituted
phenylethyl group.
 The addition of a para hydroxyl group will influence the electron density of the
phenyl ring through its ability to interact with the aromatic electrons.
Electronic Effects
The electronic effect of a functional group is measured by its ability to
either donate its electrons to adjacent atoms or functional groups or to
pull or withdraw electrons away from adjacent atoms or functional
groups.
Electron Donating Functional Groups
o Negatively charged functional groups, such as a carboxylic acid, can donate
electrons through induction.
o Second, functional groups that contain a lone pair of electrons, such as a
hydroxyl group, an aromatic amine, an aromatic thiol, or a methoxy group,
can donate electrons into a phenyl or aromatic ring system.
o Finally, alkyl groups, such as a methyl group or an ethyl group can serve as
electron donating groups through induction.
Electron Withdrawing Functional Groups
 First, halogens, a trifluoromethyl group, as well as positively charged
functional groups, such as an ionized amine, will pull or withdraw electrons
through induction.
 Second, when hydroxyl groups, sulfhydryl groups, and ether groups are not
adjacent to either an aromatic ring or a double bond system, they act as
electron withdrawing groups as a result of their inductive effects.
 Finally, can withdraw electrons through either resonance or induction.
Adjacent functional groups, as well as the presence or absence of direct
attachment to an aromatic ring, will determine the relative involvement of
these two processes.
Drug likeness  Properties
Solubility Effects
 The overall water and/or lipid solubility of a drug molecule affects its route(s)
of administration, distribution within the body, metabolism, duration of action,
and route(s) of elimination.
 Further explanations with respect to the importance of water and lipid
solubility, partition coefficients, the ability to analyze a drug molecule and
identify its water soluble and lipid soluble components, the need for a balance
between water and lipid solubility, the advantages of increasing either water or
lipid solubility, and common strategies to alter solubility in a desired direction.
Water Soluble Functional Groups
 Functional groups that enhance the water solubility of a drug molecule are
often referred to as hydrophilic functional groups.
 The two major properties that contribute to the water solubility of a
functional group are its ability to ionize and/or its ability to form hydrogen
bonds.
Drug likeness  Properties
Lipid Soluble Functional Groups
 Functional groups that enhance the lipid solubility of a drug molecule are often
referred to as hydrophobic or lipophilic functional groups.
 Functional groups that lack the ability to either ionize or form hydrogen bonds
tend to impart a measure of lipid solubility to a drug molecule.
Drug likeness  Properties
Steric Effects
 Each functional group has a finite size or steric dimension that
contributes to the overall conformation or three-dimensional shape of
a given drug molecule.
 Obviously, some functional groups are larger and more bulky than
others, and it is impossible for two atoms or functional groups to
occupy the same space.
 Additionally the size and shape of each functional group must be able
to be accommodated for by the binding sites present at its biological
target.
 The addition of functional groups to a drug molecule based primarily
upon their steric effects can provide a number of therapeutic benefits
for a drug molecule including:
• increased selectivity for its biological target
• enhanced binding interactions with its biological target
• favorable alteration of its rate of metabolism
Prodrugs
 Prodrugs have a structure that improves solubility, permeability, stability, or
targeting to a tissue in order to improve pharmacokinetics.
 The pro-moiety is cleaved in vivo to release the active structure.
 Prodrugs can improve properties when no other structural modification is
sufficient.
 The prodrug strategy is successful only a portion of the times it is used.
Drug likeness  Properties
Prodrugs to Increase Passive Permeability
 Prodrug strategies are most commonly used to increase
permeability of compounds by masking the polar
functional groups and hydrogen bonds with ester or
amide linkers and increasing lipophilicity.
 Oral delivery of ester/amide prodrugs to the therapeutic
target is confrontedwith many physiological, chemical,
and biochemical barriers.
 In general, the highest oral bioavailability values that
ester prodrugs can achieve clinically are 40% to 60%.
Ester Prodrugs for Carboxylic Acids
 Simple alkyl esters are preferred for carboxylic acid prodrugs to increase
passive diffusion permeability.
 Ethyl ester is the most common prodrug of this type.
Examples of ester prodrugs of acids used to enhance passive permeability.
Ester Prodrugs for Alcohols and Phenols
Drug likeness  Properties

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Drug likeness Properties

  • 2.   Introduction  Properties Are of Interest in Discovery  Drug discovery  Solubility  Lipinski & Veber rules  Applications of rules  Property profiling  Discovery Inefficiencies Contents
  • 3.   Drug-like is defined as those compounds that have sufficiently acceptable ADME properties and sufficiently acceptable toxicity properties to survive through the completion of human Phase I clinical trial  Drug-like properties confer good ADME/Tox characteristics to a compound.  Medicinal chemists control properties through structure modification.  Biologists use properties to optimize bioassays and interpret biological experiments. Introduction
  • 4.  Drug-like Properties Are an Integral Part of Drug Discovery The structure determines the compound’s properties.
  • 5.  When the structural properties interact with the physical environment, they cause physicochemical properties (e.g., solubility).  When the structural properties interact with proteins, they cause biochemical properties (e.g., metabolism).  At the highest level, when the physicochemical and biochemical properties interact with living systems they cause PK and toxicity.  Medicinal chemists control the PK and toxicity properties of the compound by modifying the structure. Drug-like Properties Are an Integral Part of Drug Discovery
  • 6.  Properties of interest to discovery scientists include the following: Many Properties Are of Interest in Discovery Structural properties Hydrogen bonding Polar surface area Lipophilicity Shape Molecular weight Reactivity pKa Physicochemical properties Solubility Permeability Chemical stability
  • 7.  Biochemical properties Metabolism (phases I and II) Protein and tissue binding Transport (uptake, efflux)  Pharmacokinetics (PK) and toxicity Clearance Half-life Bioavailability Drug–drug interaction LD50 Conti..
  • 8.   Before exploring how properties affect drug candidates, it is useful to briefly review the process of drug discovery and development. Introduction to the Drug Discovery and Development Process Overview of drug research and development stages and their major activities.
  • 9.  Stages of drug discovery, primary goals, and major activities.
  • 10.  Many negative effects can occur for low-solubility compounds, including the following:  Poor absorption and bioavailability after oral dosing  Insufficient solubility for IV dosing  Artificially low activity values from bioassays  Erratic assay results (biological and property methods)  Development challenges (expensive formulations and increased development time)  Burden shifted to patient (frequent high-dose administrations) Solubility
  • 11.  Solubility is the maximum dissolved concentration under given solution conditions.  Solubility is a determinant of intestinal absorption and oral bioavailability.  Increased by adding ionizable groups or reducing Log P and MW.  Salt forms increase dissolution rate. Solubility
  • 12.  Solubility Varies with Structure and Physical Conditions Solubility is determined by many factors:  Compound structure  Physical state of compound that is introduced into solution Solid: Amorphous, crystalline, polymorphic form Liquid: Predissolved in solvent (e.g., dimethylsulfoxide [DMSO])  Composition and physical conditions of solvent(s) Types of solvents Amount (%) of co-solvents Solution components (e.g., salts, ions, proteins, lipids, surfactants) pH Temperature Solubility Fundamentals
  • 13.  Methods of measurement Equilibration time Separation techniques (e.g., filter, centrifuge) Detection (e.g., ultraviolet, mass spectrometry, turbidity)  Structural Properties Affect Solubility  Solubility is affected by physicochemical properties, which can be estimated using in vitro assays or software calculations.  Lipophilicity: Determined by van der Waals, dipolar, hydrogen bonds, ionic interactions  Size: Molecular weight, shape  pKa: Determined by functional group ionizability  Crystal lattice energy: Determined by crystal stacking, melting point Conti..
  • 14. Effects of Solubility Solubility, permeability, and metabolic stability affect oral absorption and bioavailability following oral dosing.
  • 15. Example Effect of solubility on oral bioavailability.
  • 16.  The early lead compound L-685,434 had good potency in vitro in both enzyme and cell-based assays but was completely inactive in vivo after oral dosing due to poor solubility.  The compound was modified by introducing ionizable centers into the molecule to increase solubility.  The modified compound (indinavir) is much more soluble, maintains good potency, and has oral bioavailability of 60% in human.
  • 17. <10 μg/mL - Low solubility 10–60 μg/mL - Moderate solubility >60 μg/mL - High solubility In rating the solubility of compounds for discovery project teams, the following solubility classification ranges are suggested for medicinal chemists:
  • 18.  It divides compounds into four classes based on solubility and permeability The Biopharmaceutics Classification System (BCS)
  • 19.  Class I is high solubility and high permeability. This is an ideal class for oral absorption.  Class II is low solubility and high permeability. Formulation typically is used to enhance solubility of compounds in this class.  Class III is high solubility but low permeability. Pro- drug strategies typically are used for these compounds.  Class IV is low solubility and low permeability. Development of this class of compounds can be risky and costly. No in vitro/in vivo correlations are expected.
  • 20. Molecular Properties for Solubility and Permeability Effects of structural properties on solubility and permeability.
  • 21. Changing one property can affect several others.  The figure shows how structural features that enhance solubility often reduce permeability.  For example, increasing charge, ionization, or hydrogen bonding capacity will increase solubility but will decrease permeability.  Increasing lipophilicity and size to some extent will increase permeability but will decrease solubility.  Medicinal chemists must balance the different structural features to find a balance between solubility and permeability for the clinical candidate in order to achieve optimal absorption.
  • 22. Structure Modification Strategies to Improve Solubility
  • 23. Structure Modifications Strategies for Solubility Improvement
  • 24. Add Ionizable Groups  Addition of ionizable groups is commonly used for enhancing solubility.  It is one of the most effective structural modifications to increase solubility.  Typically, a basic amine or a carboxylic acid is introduced to the structure.  Compounds with an ionizable functional group will be charged in pH buffers and have increased solubility.  One example is solubility enhancement of artemisinin, which is an antimalarial agent.  The sodium salt of a carboxylic acid analog achieved higher solubility, but, in this case, the compound was unstable.  Ultimately, the amine analogs attained better solubility and stability and were active after oral dosing.
  • 25. Add Hydrogen Bonding • Introducing hydrogen bond donors and acceptors, such as OH and NH2, can enhance aqueous solubility. • Two anti-AIDS agents are shown. • The first compound has poor aqueous solubility and poor oral bioavailability, which limited its further development. • Introducing a hydroxyl group into the molecule increased solubility and oral bioavailability.
  • 26. Reduce Log P  Several protease inhibitors are shown Reducing Log P increased solubility and led to higher systemic exposure, as indicated by enhanced maximum concentrations in the blood, Cmax.  Reducing Log P and increasing solubility enhances the in vivo exposure.
  • 27. Add Polar Group  Water solubility usually increases with the addition of a polar group.  A series of epoxide hydrolase inhibitors.  Solubility increased with the introduction of the ester group (more polar) and carboxylic acid group (more polar and ionizable). Reduce Molecular Weight  Reduction in molecular weight is another useful approach for increasing solubility.  An example of CDK2 inhibitors.  The lower molecular weight increased solubility and metabolic stability, while maintaining in vitro activity.  In vivo potency was improved because of the increased solubility and stability.
  • 28. Out-of-Plane Substitution  Out-of-plane substitutions are illustrated in Figure.  Addition of the ethyl group shifts the planarity of the molecule, resulting in a disruption of the crystal packing to form a higher-energy crystal that is more soluble.
  • 29. Construct a Prodrug  Charged or polar groups can be added to make prodrugs with increased aqueous solubility.  In figure shows fosphenytoin, which is a prodrug of phenytoin.  The phosphate group greatly increases the solubility, making it much easier to formulate for clinical dosing.  Enzymatic hydrolysis in the intestine releases phenytoin for absorption.
  • 30. Bioavailability (F) • One of the most commonly used PK parameters is bioavailability (F). • It is the fraction of the dose that reaches systemic circulation unchanged. • Less than 100% bioavailability typically results from incomplete intestinal absorption or first-pass metabolism. • Secondary causes include enzymatic or pH-induced decomposition in the intestine or blood. Bioavailability is calculated from the expression:
  • 31. Metabolic Stability • Metabolism is the enzymatic modification of compounds to increase clearance. • It is a determinant of oral bioavailability, clearance, and half-life in vivo. • Metabolism occurs predominantly in the liver, and some may occur in the intestine. • Metabolic stability is increased by structure modifications that block or sterically interfere with metabolic sites or withdraw electrons.
  • 32. Scheme for in vitro assessment of diverse stability challenges during drug discovery.
  • 33. Drug stability can be broadly divided into two main areas: stability after administration shelf-life Stability after administration A drug will only be effective if, after administration, it is stable enough to reach its target site in sufficient concentration to bring about the desired effect. However, as soon as a drug is administered the body starts to remove it by metabolism. Consequently, for a drug to be effective it must be stable long enough after administration for sufficient quantities of it to reach its target site. In other words, it must not be metabolised too quickly in the circulatory system. Three strategies are commonly used for improving a drug’s in situ stability, namely: • Modifying its structure; • Administering the drug as a more stable prodrug • Using a suitable dosage form
  • 34. Shelf-life  Shelf-life is the time taken for a drug’s pharmacological activity to decline to an unacceptable level.  This level depends on the individual drug and so there is no universal Specification.  However, 10 per cent decomposition is often taken as an acceptable limit provided that the decomposition products are not toxic.
  • 35. Metabolic Stability Effects  Metabolic stability affects pharmacokinetics (PK), as shown in Figure.  Metabolic stability has an inverse relationship with clearance (Cl).  A decrease in metabolic stability leads to an increase in clearance.  Cl and volume of distribution (Vd) directly affect the PK half-life (t½ = 0693×Vd/Cl), which determines how often the dose must be administered. Effects of metabolic stability on pharmacokinetics.
  • 36.   Once a target and a testing system have been chosen, the next stage is to find a lead compound—a compound which shows the desired pharmacological activity.  The level of activity may not be very great and there may be undesirable side effects, but the lead compound provides a start for the drug design and development process. Finding a lead compound
  • 37.  For example the antidiabetic agent tolbutamide, which was developed from a sulfonamide structure.  Most sulfonamides are used as antibacterial agents, but some proved unsatisfactory since they led to convulsions brought on by hypoglycaemia (low glucose levels in the blood).  Structural alterations were made to eliminate the antibacterial activity and to enhance the hypoglycaemic activity and this led to tolbutamide. Tolbutamide.
  • 38.  Analog is a compound having a structure similar to that of another compound, but differing from it in respect of certain component.  In drug discovery either a large series of structural analogs of an initial lead compound are created and tested as part of a structure-activity relationship study or a database is screened for structural analogs of a lead compound. Analog
  • 39. Lipinski Rules  It is important to keep in mind the intended purpose of the rule of 5.  The article states: Poor absorption or permeation is more likely when: 1. There are more than 5 hydrogen bond donors (expressed as the sum of all OH and NH groups) 2. MWt greater than 500 3. logP greater than 5 4. There are more than 10 hydrogen bond acceptors (expressed as the sum of all Ns and Os) 5. Substrates for biological transporters are exceptions to this rule
  • 40. THE RULES WERE SET AT THE 90th PERCENTILE OF THE COMPOUND SET  This means that 90% of the compounds that had sufficient absorption after oral dosing had molecular property values within the Lipinski Rules  Compounds that approach or exceed these values have a higher risk of poor absorption after oral dosing The rules are based on a strong physicochemical rationale  Hydrogen bonds increase solubility in water and must be broken in order for a compound to permeate the lipid bilayer membrane  Thus increasing the number of hydrogen bonds reduces partitioning from the aqueous phase into the lipid bilayer membrane for permeation by passive diffusion
  • 41.  Increasing logP decreases aqueous solubility which reduces absorption  Membrane transporters can either enhance or reduce compound absorption by either active uptake transport or efflux respectively  This means that transporters can have a strong impact on increasing or decreasing absorption THE LIPINSKI RULES • are widely used as a filter and measurement of the drug-likeness of a series of molecules. • They are used to such an extent that they almost ‘copyright’ the field of drug- likeness compound scoring. • However, other experiments have also been carried out in this area….
  • 42. VEBER RULES  The results of an experiment performed by Veber et al.* examining the oral bioavailability of potential drug candidates in the rat let to the conclusion that other parameters existed for the description of drug likeness than the Lipinski rules.  The main parameter taken into account during this experiment was the number of rotatable bonds – as an indication of molecular flexibility.  Veber’s experiments indicated that the main factor influencing the possibility of uptake by the lumen is not molecular weight but, in fact the number of rotatable bonds.  This could be explained by the entropic cost of presenting an acceptable drug surface area to hydrophobic surface of the membrane in the sense that a compact molecule is easier to absorb than extended one.
  • 43.  They therefore suggest the following filter for drug-likeness: Rotatable bonds < 12 Polar surface area < 140  Also, Veber et al. (2002) therefore raise the issue of molecular weight being a proper descriptor for absorption measurement as molecular weight might just be positively correlated with more precise properties like the rotatable bonds count, polar surface area and hydrogen bonds count.  The Veber et al. experiments referred to above underline the difficulties met with when trying to make generalizing rules for complex systems.
  • 44. CORRESPONDENCE BETWEEN MOLECULAR WEIGHT, THE NUMBER OF ROTATABLE BONDS AND THE DEGREE OF BIOAVAILABILITY IN THE RAT
  • 45. Application of Rules for Compound Assessment Rules are typically used for the following purposes: • Anticipating the drug-like properties of potential compounds when planning synthesis • Using the drug-like properties of “hits” from HTS as one of the selection criteria • Evaluating the drug-like properties of compounds being considered for purchase from a compound vendor
  • 46. Example of counting and calculations for the Lipinski and Veber rules for doxorubicin, which has an oral bioavailability of approximately 5%.
  • 47. Property Profiling in Discovery  Property profiling should be rapid and use relevant assay conditions.  Use a diverse set of assays that have high impact for the organization.  Property assays consume resources and influence projects, so assays should be carefully implemented.  Evaluate the cost versus benefit of assays. Property Data Should be Rapidly Available • In order for property data to be relevant for discovery, they need to be reported to project teams rapidly. • This allows decisions to be made rapidly so that aggressive discovery time lines can be met. • Faster data allow more iterations of trying new ideas to optimize the compounds, thus increasing the success rate. • A general guide is to provide data in a few days to 2 weeks, the same time frame as biological data.
  • 48. Use Relevant Assay Conditions • The conditions of property assays need to be relevant to the environment faced by the compound. • Variables, such as concentration, pH, matrix components in solution, and biological tissue extracts, must be controlled and designed to be reflective of the barriers faced by the compound. Evaluate the Cost-to-Benefit Ratio for Assays • In any discovery organization there are always tradeoffs on the allocation of resources. • Thus, it is important to decide which properties are of greatest importance to the organization. • The properties that have the greatest impact on the projects and goals of the organization should prevail. • Assays should not be put in place because other organizations have them but should be decided based on what the organization considers to be the critical issues.
  • 49. Choose an Ensemble of Key Properties to Evaluate Each organization must select the properties they are most interested in monitoring. For example, Use Well-Developed Assays • Data used for decision-making should be generated using assays that have been well developed. • The assay conditions can greatly affect the results.
  • 50. Poor Drug Properties Also Cause Discovery Inefficiencies • Once late-discovery biopharmaceutical assessment was in place and an attrition burden was lifted from development, another discovery need was revealed. • Candidates that were failing in late discovery because of poor properties still caused a great burden on drug discovery. • Failure late in discovery meant that the project to discover a new drug had lost valuable time and resources on the failed candidate and had to start over. Marginal Drug Properties Cause Inefficiencies During Development • Although the rate of outright candidate failure in development has decreased due to early termination of candidates with inadequate properties, candidates with marginal properties still progress into development. • Even though they might not fail in development, they impose significant inefficiencies on development by increasing development costs and prolonging development time lines.
  • 51. Following are examples of how poor drug properties can reduce the quality of drug discovery biological research: • Low or inconsistent bioactivity responses for in vitro bioassays can be due to precipitation, owing to low solubility of the compound in the bioassay medium or in dilutions prior to the assay. • Low activity in bioassays may be due to chemical instability of the compound in the test matrix. • An unexpectedly high drop in activity can result when transitioning from enzyme or receptor activity assays to cell-based assays. This can be due to poor permeability of the compounds through the cell membrane, which must be penetrated for the compound to reach intracellular targets. • Compounds may be unstable or insoluble in the DMSO solutions that are stored in microtiter plates and experience freeze–thaw cycles, or they may be exposed to various physicochemical conditions in the laboratory. • Poor efficacy of a central nervous system (CNS) drug in vivo may be due to poor penetration of the blood–brain barrier. • Poor efficacy in vivo may be due to low concentrations in the plasma and target tissue because of poor PK, low bioavailability, or instability in the blood.
  • 52. WHAT IS A FUNCTIONAL GROUP? Functional groups provide specific properties and behaviors that allow drug molecules to exert their desired pharmacodynamic and pharmacokinetic effects. For a given drug molecule they play a significant role in the: • Overall water/lipid solubility • Route of administration • Ability to interact with specific biological targets • Mechanism of action • Route of metabolism and elimination • Duration of action • Suitability for a specific therapeutic situation • Tendency to cause adverse effects or drug interactions
  • 53. • When examining drug molecules, there are three overriding concepts that you should always consider. • First, every atom within the structure of a drug molecule is part of a specific functional group. • example of this concept by using the nonsteroidal anti-inflammatory agent, indomethacin.
  • 54. CHEMICAL PROPERTIES OF FUNCTIONAL GROUPS  There are three major chemical properties that need to be considered for every functional group.  Each functional group has an electronic effect, a solubility effect, and a steric effect that needs to be considered when evaluating the overall pharmacodynamic and pharmacokinetic properties of any given drug molecule.  Prior to proceeding, there are two key points to keep in mind.  First of all, the addition of a single functional group to a given molecule will affect the overall electronics, solubility, and steric dimensions of that molecule.  It is impossible for a functional group to alter only one of these properties.  As an example, consider a drug molecule that contains an unsubstituted phenylethyl group.  The addition of a para hydroxyl group will influence the electron density of the phenyl ring through its ability to interact with the aromatic electrons.
  • 55. Electronic Effects The electronic effect of a functional group is measured by its ability to either donate its electrons to adjacent atoms or functional groups or to pull or withdraw electrons away from adjacent atoms or functional groups.
  • 56. Electron Donating Functional Groups o Negatively charged functional groups, such as a carboxylic acid, can donate electrons through induction. o Second, functional groups that contain a lone pair of electrons, such as a hydroxyl group, an aromatic amine, an aromatic thiol, or a methoxy group, can donate electrons into a phenyl or aromatic ring system. o Finally, alkyl groups, such as a methyl group or an ethyl group can serve as electron donating groups through induction.
  • 57. Electron Withdrawing Functional Groups  First, halogens, a trifluoromethyl group, as well as positively charged functional groups, such as an ionized amine, will pull or withdraw electrons through induction.  Second, when hydroxyl groups, sulfhydryl groups, and ether groups are not adjacent to either an aromatic ring or a double bond system, they act as electron withdrawing groups as a result of their inductive effects.  Finally, can withdraw electrons through either resonance or induction. Adjacent functional groups, as well as the presence or absence of direct attachment to an aromatic ring, will determine the relative involvement of these two processes.
  • 59. Solubility Effects  The overall water and/or lipid solubility of a drug molecule affects its route(s) of administration, distribution within the body, metabolism, duration of action, and route(s) of elimination.  Further explanations with respect to the importance of water and lipid solubility, partition coefficients, the ability to analyze a drug molecule and identify its water soluble and lipid soluble components, the need for a balance between water and lipid solubility, the advantages of increasing either water or lipid solubility, and common strategies to alter solubility in a desired direction. Water Soluble Functional Groups  Functional groups that enhance the water solubility of a drug molecule are often referred to as hydrophilic functional groups.  The two major properties that contribute to the water solubility of a functional group are its ability to ionize and/or its ability to form hydrogen bonds.
  • 61. Lipid Soluble Functional Groups  Functional groups that enhance the lipid solubility of a drug molecule are often referred to as hydrophobic or lipophilic functional groups.  Functional groups that lack the ability to either ionize or form hydrogen bonds tend to impart a measure of lipid solubility to a drug molecule.
  • 63. Steric Effects  Each functional group has a finite size or steric dimension that contributes to the overall conformation or three-dimensional shape of a given drug molecule.  Obviously, some functional groups are larger and more bulky than others, and it is impossible for two atoms or functional groups to occupy the same space.  Additionally the size and shape of each functional group must be able to be accommodated for by the binding sites present at its biological target.  The addition of functional groups to a drug molecule based primarily upon their steric effects can provide a number of therapeutic benefits for a drug molecule including: • increased selectivity for its biological target • enhanced binding interactions with its biological target • favorable alteration of its rate of metabolism
  • 64. Prodrugs  Prodrugs have a structure that improves solubility, permeability, stability, or targeting to a tissue in order to improve pharmacokinetics.  The pro-moiety is cleaved in vivo to release the active structure.  Prodrugs can improve properties when no other structural modification is sufficient.  The prodrug strategy is successful only a portion of the times it is used.
  • 66. Prodrugs to Increase Passive Permeability  Prodrug strategies are most commonly used to increase permeability of compounds by masking the polar functional groups and hydrogen bonds with ester or amide linkers and increasing lipophilicity.  Oral delivery of ester/amide prodrugs to the therapeutic target is confrontedwith many physiological, chemical, and biochemical barriers.  In general, the highest oral bioavailability values that ester prodrugs can achieve clinically are 40% to 60%.
  • 67. Ester Prodrugs for Carboxylic Acids  Simple alkyl esters are preferred for carboxylic acid prodrugs to increase passive diffusion permeability.  Ethyl ester is the most common prodrug of this type. Examples of ester prodrugs of acids used to enhance passive permeability.
  • 68. Ester Prodrugs for Alcohols and Phenols