Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally...
Transcript of Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally...
![Page 1: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/1.jpg)
Foundations of Pharmaceutical Science
![Page 2: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/2.jpg)
Foundations of Pharmaceutical Science
(Voigt) (Hass, Voigt, Balaz)
(Hass, Cen)
![Page 3: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/3.jpg)
Medicinal Chemistry
Discipline of chemistry focused on the influence of chemical structure on the delivery and pharmacological activity and metabolism of drug molecules
Related Disciplines:• Organic Chemistry• Biochemistry• Pharmacology• Pharmaceutics
![Page 4: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/4.jpg)
Medicinal Chemistry
Organic Chemistry• Drug Structure (Functional Groups, Stereochemistry,
Physiochemical Properties)• Structure-Activity Relationships• Drug Design and Development
Biochemistry• Drug Transport• Enzymes and Enzyme Activity • Endogenous Compounds
![Page 5: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/5.jpg)
Pharmacology (Pharmacodynamics)• Drug-Receptor Interactions and Signal Transduction• Dose-Response (Potency, Efficacy)• Mechanism of Action
Pharmaceutics (ADME; Pharmacokinetics)• Drug administraton and absorption• Drug distribution• Drug metabolism and excretion
![Page 6: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/6.jpg)
Bioavailability• The extent (how much) and the rate (how fast) that the
active drug or drug metabolite reaches the systemic circulation/target site of action. action.
• Factors influencing bioavailability• Drug structure/physiochemical properties• Mode of administration• Formulation• Drug/food interactions• Disease state• Individual metabolic differences
![Page 7: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/7.jpg)
Chemical Structure & Pharmacologic Activity
Pharmacophore
The minimum structural elements, functional groups and 3D arrangement of a compound necessary to cause a biological response
Non-essential parts of the molecule are referred to as auxophore(s)
Pharmacophore revealed through systematic structural modification and pharmacologic testing
![Page 8: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/8.jpg)
N
OH
OH
H3C
Levorphanol(morphinan)
HO
N
O OH
OH
H3C
Morphine
remove dihydrofuran
(analgesic, addictive)
(4X more potent analgesic, retains addictive properties)
N
OH
H3C
Benzomorphan
remove cyclohexene
(less potent than morphine but also less addictive)
NH3C
Meperidine(10-12% less potent than morphine but also less addictive)
O
OCH2CH3
remove cyclohexane
![Page 9: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/9.jpg)
Influence of Drug Structure
Physiochemical properties of drugs refers to the influence of functional groups on:
polarityionizationsolubility
molecular shape
These factors influence pharmacokinetics and pharmacodynamics
![Page 10: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/10.jpg)
Drug Polarity
Polarity of a drug refers to the extent of charge separation in a molecule.
• Factors that decrease polarity (lipophilic)– Hydrocarbon elements
• Factors that increase polarity of a drug include:(hydrophilic)– Formal charges (ionization)– Polar covalent bonds– Lone pair electrons– Hydrogen bonding
![Page 11: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/11.jpg)
Drug Polarity
N
N
N
H O
OOH
N
H
N
O
S
O
OH
Apalicillin(antibacterial)
lipophilic region
hydrophilic region
Both lipophilic and hydrophilic regions are present within most drug molecules
![Page 12: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/12.jpg)
Drug Polarity
N
O
OCH3
CH3
Femoxetine
δ+
δ−
δ−
δ−
δ−
Polar covalent bonds and lone pair electrons contribute to drug polarity
![Page 13: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/13.jpg)
Drug Polarity
Ionizable functional groups have the potential of contributing to polarity by generating a formal charge
N
N
N
H O
OOH
N
H
N
O
S
O
OH
Apalicillin(antibacterial)
O
OR
ionizable functional group
![Page 14: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/14.jpg)
Drug Polarity
Substituents can influence pKa and ionization
O
O
H
EWG
EWG = electron-withdrawing group(i.e., nitro)
δ+
O
O
EWG
δ+
EWG: Stabilizes conjugate baseincreases Ka, decreases pKa
decrease electron density around ring by resonance or inductive
effects
O
O
H
EDG
EDG = electron-donating group(i.e., halogens)
δ−
O
O
EDG
δ−
EDG: Destabilizes conjugate basedecreases Ka, increases pKa
increase electron density around ring by resonance or inductive
effects
![Page 15: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/15.jpg)
Drug PolarityHydrogen bonding
H-bonds are weak interactions that occur between a H atom (bonded to an electronegative element) and the lone pair electrons of another atom within the same molecule (intramolecular) or another molecule (intermolecular).
O
O
O
O CH3
H
intramolecular H-bond
intermolecular H-bond
O
O
O
O CH3
H
O
O
O
O CH3
H
![Page 16: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/16.jpg)
Polarity and Non-Covalent Bonding Interactions
• Non-covalent interactions are weak interactions between functional groups of like polarity within (intra) or between (inter) molecules
• Types of non-covalent interactions include:– H-bonds– Dipole-dipole– Ion-dipole– Hydrophobic Interactions
![Page 17: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/17.jpg)
Polarity and Non-Covalent Bonding Interactions
Cl
O N
Toremifene
δ+δ+ δ−
δ−
δ−
Cl
O Nδ+δ+
δ−δ−
δ−
Dipole-Dipole
H3COOCH3
OH3C
O
OOCH3
δ+
δ−
δ−folding
Intermolecular
Intramolecular
![Page 18: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/18.jpg)
Polarity and Non-Covalent Bonding Interactions
O
CH3
O
NH3C
H3C CH3 δ−
δ− δ+
O
CH3
O
NH3C
H3C CH3 δ−
δ− δ+
Ion-Dipole
O
CH3
O
N
H3CCH3
CH3
δ−
δ+
Intermolecular
Intramolecular
![Page 19: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/19.jpg)
Polarity and Non-Covalent Bonding Interactions
H2N
HN
OH
O
O
H2N
HN
OH
O
O
Hydrophobic
H2NNH
O
O
OH
Intermolecular
Intramolecular
![Page 20: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/20.jpg)
Polarity and Water Solubility
O
CH3
O
NH3C
H3C CH3 δ−
δ−
δ+O
H H
HO
H
HO
H
δ+
δ−
Hydrogen bonding and ion-dipole bonding contribute to water solubility
Intermolecular H-bonding between drug functional groups and water increases water solubility
Intramolecular H-bonding or ion dipole bonding within a drug does not allow solvation by water and diminishes water solubility
O
CH3
O
N
H3CCH3
CH3
δ−
δ+
![Page 21: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/21.jpg)
Molecular Shape
OOH
A B C Receptor
Specific functional groups on drug bind to specific sites on receptor.Groups must be oriented properly to accommodate specific binding
![Page 22: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/22.jpg)
Molecular Shape
• Spatial arrangement of functional groups influences physiochemical properties of drugs
• Isomers, molecules with the same molecular formula but different structural arrangement of atoms, have different physiochemical and pharmacologic properties
![Page 23: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/23.jpg)
Isomers
Drug isomers have the same molecular formula with a different arrangement of atoms
Isomers
Constitutional Configurational
Skeletal PositionalFunctionalgroup
Conformational
Stereoisomers
Enantiomers Diastereomers
![Page 24: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/24.jpg)
Stereochemistry
• Two general types of stereoisomers:
– Configurational: same structural formula except different arrangement of atoms around a chiral element in the molecule (enantiomers, diastereomers, cis/trans isomers)
– Conformational: same structural formula different spatial arrangements due to rotation around sigma bonds
![Page 25: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/25.jpg)
Stereochemistry
Configurational
Diastereomers Enantiomers
Conformational
Stereoisomers
![Page 26: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/26.jpg)
Geometric Isomers
OH
AH
H
C
BA
B
C
OH
AB
C
H
H
AB
C
Differences in 3D orientation of functional groups results in different receptor binding
A C A C
H H
A C
A H
H C
(cis/trans; E/Z; syn/anti)
![Page 27: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/27.jpg)
Enantiomers• Non-superimposable mirror image isomers that arise due to the
chirality of an atom or of the overall molecule. Referred to as R/S, D/L or d/l (dextro/levo) isomers
• Enantiomers have identical physical properties (i.e., energy, boiling point, melting point, densities, etc.) except that they rotate the plane of polarized light in different directions.
• Enantiomeric drugs do not necessarily have the same biological activity, and often have very different biological activity.
• Many drugs are sold as racemic mixtures. Racemic mixtures are 50:50 mixtures of enantiomers. FDA requires that individual enantiomers be separated and tested for biological activity even if the drug is to be sold as a racemate.
![Page 28: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/28.jpg)
Enantiomers
• d- Propoxyphene (DARVON) and l- propoxyphene (NOVRAD) are enantiomers
• The d- isomer (trade name DARVON) is a narcotic analgesic. Its l-enantiomer is NOVRAD which is an antitussive agent (cough suppressant)
O
O
O
N
O
N
(+) propoxyphene
(DARVON)
(-) levopropoxyphene
(NOVRAD)
![Page 29: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/29.jpg)
Enantiomers
AB
C AB
C
D
A BC
B
A DC
Differences in 3D orientation of functional groups around chiral center results in different receptor binding and different pharmacological activity
![Page 30: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/30.jpg)
Diastereomers
• Diastereomers are non-superimposable, non-mirror image stereoisomers.
• Diastereomers arise in molecules with more than one chiral center or chiral element
• Diastereomers have different physical properties and different pharmacological activity
![Page 31: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/31.jpg)
Enantiomers & Diastereomers
NH
OO
N
O
OHO
Enalapril(antihypertensive)
* *
*
NH
OO
N
O
OHO
enantiomer of enalapril
NH
OO
N
O
OHO
diastereomer of enalapril
Molecules with more than one chiral center can have both enantiomers and diastereomers.
![Page 32: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/32.jpg)
Conformational Isomers
• Conformers are isomers which arise due to rotation about a carbon-carbon single bond.
• Rotation around carbon-carbon single bonds may occur without any breaking of covalent bonds.
• Some conformers or conformational isomers may experience unfavorable interactions which give rise to higher energy conditions.
![Page 33: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/33.jpg)
Conformational Isomers
C C
HH 3C
H H
H H
C C
HH
H H
CH 3 H
![Page 34: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/34.jpg)
Conformational Isomers
X
C
ZY
A BA
B
C
B
C
ZY
X AA
B
C
![Page 35: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/35.jpg)
Conformational Isomers
O
HHH H
O
CH3
N
H H
N
OO
CH3
HH
Ester-binding site
Hydrophobic bindingsite
Anionic-bindingsite
Ester-binding site
Hydrophobic bindingsiteAnionic-binding
site
Acetylcholine conformers
![Page 36: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/36.jpg)
Structure Activity Relationships (SAR)
• Structurally specific drugs (majority)
– act at a specific target site such as a receptor or enzyme to produce a biological effect
– modification of structure gives rise to modification in activity (SAR)
• Structurally nonspecific drugs– no specific site of action– less dependence of activity on specific drug structure
![Page 37: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/37.jpg)
Drug DiscoveryStructure Modification
O
HOH
CCH
O
CH3
CH3
O
CH3
progesterone norgestrel
HO
OH
CCH
17α-ethynyl estradiolHO
OH
H
estradiol
Endogenous Synthetically Modified
Highlighted portions of molecules illustrate auxophores
![Page 38: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/38.jpg)
Structure Activity Relationships (SAR)OHO
O
OAcOH
O
AcO
O
O
OH
NH
O
paclitaxol
A
B
C
DE
F
G
H
I
J
A N-acyl group required F Change of stereochemistry or esterification does not change activity
B Phenyl or analog required G Oxetane or other small ring required for activity
C Free hydroxyl or hydrolyzable group required H Removal of acetoxy reduces activity; other acyl analogs have improved activity
D Acetoxy may be removed w/out loss of activity
I Acyloxy required; substituted benzyloxy improves activity
E Reduction of ketone improves activity slightly
J Removal of hydroxyl reduces activity slightly
![Page 39: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/39.jpg)
Qualitative and Quantitative SAR
• Structural Modification of Lead Compounds(Qualitative SAR)– Homologation– Chain branching– Ring/chain transformations– Positional isomerization– Bioisosterism (“functional group equivalents”)
• Structural modification results in changes to pharmacodynamics (affinity, efficacy, potency) and pharmacokinetics (ADME)
![Page 40: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/40.jpg)
Structural Modification of Lead CompoundsHomologation
• Homologation refers to progressive increases in hydrocarbon chain length(-CH2 units; methyl, ethyl, propyl, etc)
• General trend is an increase followed by a decrease in activity that correlates with lipophilicity (log P)
• Increase in activity correlates with greater bioavailability. Decrease in activity occurs when reduced water solubility interferes with transport in aqueous media or formation of micelles
1 2 3 4 5 6 7 8 9 10 11 12
Hydrocarbon chain length
activity
micelle
![Page 41: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/41.jpg)
Structural Modification of Lead CompoundsHomologation
R
OH
OH
4-Alkylresorsinol antibacterial activityR = n-propyl (5%); n-butyl (22%);
n-pentyl (33%); n-hexyl (51%);n-heptyl (30%); n-octyl (0%)
![Page 42: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/42.jpg)
Structural Modification of Lead CompoundsChain Branching
• Branching imposes steric changes that affect receptor binding
• Chain branching in the aminoalkylphenothiazines promethazine and promazine results in binding to different receptors
N
S
N
N
S
N
1
23
12
3
branched straight chain
promethazine promazine
ANTIPSYCHOTICANTIHISTAMINE
![Page 43: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/43.jpg)
Structural Modification of Lead CompoundsRing Chain Transformations
• Ring chain transformations generally provide conformational rigidity (in the ring) and conformational flexibility (in the chain)
• Ring structures in local anesthetics enhance binding at active sites in the receptor by “holding” groups in place
N N
CH3
CH3
CH3
CH3
NH
O
N
Ring Chain
CH3
CH3
NH
O
NH3C
Chain
Lignocaine MepivacaineIsogramine
Lipophilic
DipoleAnionic
![Page 44: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/44.jpg)
Structural Modification of Lead CompoundsPositional Isomerization
• Altering the position of functional groups modifies receptor binding and changes pharmacokinetics
• Replacement of the cathechol moeity of adrenergic agents with a resorcinol moeity enhances selectivity for β2-adrenergic receptors
• Resorcinol derivatives have longer duration of action since the COMT enzyme does not metabolize these compounds
HO
HO
NHR
OH
Norepinephrine R = HEpinephrine R = CH3
cathechol
COMT(catechol O-methyltransferase)
H3CO
H3CO
NHR
OH
HO NH
OH
OH Metaproterenol
resorcinol
COMT(catechol O-methyltransferase)X
H3CO NH
OH
OCH3
![Page 45: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/45.jpg)
Structural Modification of Lead CompoundsBioisosterism
• Bioisosteres are substituents or functional groups with steric and electronic similarities that produce broadly similar biological properties
• Two types of bioisosteres– Classical isosteres– Non-classical isosteres
![Page 46: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/46.jpg)
Structural Modification of Lead CompoundsBioisosterism
![Page 47: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/47.jpg)
Structural Modification of Lead CompoundsBioisosterism
• Non-classical Isosteres– substitution of
substituents with groups not defined by classical isosteric terms but still bear steric and electronic similarities
![Page 48: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/48.jpg)
Quantitative Structure Activity Relationships
• Electronic effects (Hammett equation)– assigns value (σ) to substituents to account for
electron donating/electron withdrawing character of substituents based on inductive and resonance effects
• Lipophilicity and partition coefficient (Hansch equation)– assigns value (P) to molecules to account for
lipophilic character
• Steric Effects (Taft Equation)– assigns value (E) to substituents to account for steric
effects
![Page 49: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/49.jpg)
Quantitative Structure Activity RelationshipsElectronic effects (Hammett equation)
EWD = electron-withdrawing groupEDG = electron-donating group
Electronic Effects
Resonance effects-alters electron density via
delocalization of pi electrons
Inductive Effects-alters electron density based on
differences in electonegativity (EN)
EWG-atom directly bonded to parent
part of another pi system
EDG-atom directly bonded to parent
has lone pair
EWG-atom directly bonded to parent more EN
![Page 50: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/50.jpg)
Quantitative Structure Activity RelationshipsElectronic effects (Hammett equation)
Both inductive and resonance effects contribute to a substituent’s ability to be an EDG or EWG.
H3CO
R R
OCH3
H3CO
R R
OCH3
para meta
H3CO
R
R
OCH3
δ−
δ+
δ+
δ−
RESONANCE INDUCTION
![Page 51: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/51.jpg)
Quantitative Structure Activity RelationshipsElectronic effects (Hammett equation)
• For meta and para substituted benzoic acids, Hammett showed a linear relationship between the ED-ability/EW ability of a substituent and the Ka of the acid (ortho- skewed by steric effects and does not correlate)
log Ka
log
k
p-NO2
m-NO2m-Cl
p-Cl
p-F
m-CH3
o-NO2
o-Clo-F
p-OCH3
log kslog k0
= σρ
σ = electronic parameter (substituent) ρ = reaction constant
ks = rate of ionization for substituent k0 = rate of ionization for H
![Page 52: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/52.jpg)
Quantitative Structure Activity RelationshipsElectronic effects (Hammett equation)
• The σ values are used to predict electron-donating and electron-withdrawing character of substituents in drugs
• The σmeta values follow inductive trend; σ para follow resonance trend
• Values are additive and constitutive
Substituent Abbreviation σ meta σ para
acetamido- AcNH- 0.21 -0.01
acetoxy- AcO- 0.39 0.31
acetyl- Ac- 0.38 0.50
amino- NH 2- -0.16 -0.66
bromo- Br- 0.39 0.23
tert-butyl- (CH 3)3C- -0.10 -0.20
chloro- Cl- 0.37 0.23
cyano- NC- 0.56 0.66
ethoxy- EtO- 0.10 -0.24
ethyl- Et- -0.07 -0.15
fluoro- F- 0.34 0.06
hydrogen H- 0.00 0.00
hydroxy- HO- 0.12 -0.37
methoxy- MeO- 0.12 -0.27
methyl- Me- -0.07 -0.17
nitro- NO2- 0.71 0.78
phenyl- Ph- 0.06 -0.01
trifluoromethyl F3C- 0.43 0.54
trimethylamino- (CH 3)3N +- 0.88 0.82
![Page 53: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/53.jpg)
Quantitative Structure Activity RelationshipsLipophilicity and Partition Coefficient
• Partition coefficient (lipophilicity) can be correlated with biological activity
• Three models– linear– parabolic– bilinear
log
1/B
R
log P0-4 4-2 2
4
-4
-2
0
2
![Page 54: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/54.jpg)
Quantitative Structure Activity RelationshipsLipophilicity and Partition Coefficient (Hansch)
• Lipophilic character of specific substituents can be determined and correlated with the partition coefficient
• The value π is used to indicate lipophilic character of specific substituents
Substituent π
H 0.00
-CH 3 0.56
-CH 2CH 3 1.02
-CH 2CH 2CH 3 1.55
-C(CH 3)3 1.53
-OCH 3 -0.02
-NH 2 -1.23
-F 0.14
-Cl 0.71
-Br 0.86
-I 1.12
-CF3 0.88
-OH -0.67
-COCH 3 -0.55
-NHCOCH 3 -0.97
-NO2 -0.8
-CN -0.57
![Page 55: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/55.jpg)
Quantitative Structure Activity RelationshipsLipophilicity and Partition Coefficient (Hansch) equation)
The partition coefficient (lipophilicity) of a compound can be calculated from π values of its substituents
diethylstibestrol
OH
HO
log P = 2πCH3 + 2πCH2 + πCH=CH + 2logPPhOH
= 2(0.50) + 2(0.50) + 0.69 + 2(1.46) = 5.61
Experimental log P = 5.07
![Page 56: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/56.jpg)
Quantitative Structure Activity RelationshipsSteric Effects (Taft Equation)
• Taft Equation-Es represents the steric contribution of a particular group based on rates of hydrolysis α-substituted acetates
Es = logkxCO2Me – logkmethyl acetate
H3C
O
OCH3
H+
H2O H3C
O
OH
+ HOCH3
X
O
OCH3
H+
H2O X
O
OH
+ HOCH3
k = rate constant for acid catalyzed hydrolysis
![Page 57: Foundations of Pharmaceutical ScienceStructure Activity Relationships (SAR) • Structurally specific drugs (majority) – act at a specific target site such as a receptor or enzyme](https://reader034.fdocuments.us/reader034/viewer/2022042117/5e95d5a9c30c1b427c557ec9/html5/thumbnails/57.jpg)
Quantitative Structure Activity RelationshipsSteric Effects (Taft Equation)
N
H
N
CH3
CH3
Cl
S(+)-dexchlorpheniramine
N
H
Cl
N
CH3
CH3
R(-)-dexchlorpheniramine
The S-enantiomer is 200 times more potent than the R as 1H receptor antagonist.
How does changing the sterics affect potency?