Balancing Potency and Physicochemical Properties

 Potency is primarily driven by hydrophobic interactions (lipophilic components of the drug

interacting with hydrophobic pockets on the target). Hydrophilic interactions (primarily H-
bonding interactions) facilitate shape complementarity.

Phe 169 Met 109

pocket Asp N
Thr H
168
106 ATP
N Binding interactions
NH site
between p38 kinase
OH
O O H and a potent inhibitor
O N
S S
N N O
H O H
O O
kinase
Glu71 specificity pocket

 Chemists often improve potency by adding additional lipophilic groups to the molecule.
However increased lipophilicity increases the chance of poor metabolic stability, off target
effects, and decreased aqueous solubility.

 Past complaint: Chemists initially concentrate on improving potency and then later pay
attention to improving other properties (PK, safety, physicochemical properties).

 Current practice: Chemists pay attention to improving potency and physicochemical

properties simultaneously from the beginning (a balancing game).
 Rule of 5 and the Rule of 3

Ro5 ('Drug-like')* Ro3 ('Lead-like')**

MW ≤ 500 ≤ 300

# H-bond donors ≤5 ≤3

# H-bond acceptors ≤ 10 ≤3

clogP ≤5 ≤3

* Good absorption or permeation are more likely when......(see Lipinski, C.A.; et al.
Advanced Drug Delivery Reviews 2001, 46, 3-26)
** Congreve, M.; et. al. Drug Disc. Today 2003, 8, 876-877.
biw80ab
 Biopharmaceutical Barriers to Drug Action
Properties affecting oral bioavailability and intestinal absorption via passive diffusion

Property Rule of 51 Averages for marketed oral drugs2

Aqueous solubility
≤ 5 (ClogP) 2.5 (ACD logP)
Lipid solubility
# H-bond donors ≤5 2.1
# H-bond acceptors ≤ 10 4.9
Molecular weight ≤ 500 337
Drug ionization 1.0 (ACD logD7.4)
Rotatable bonds 5.9
Metabolic stability

1
Rof5 defines 4 simple physicochemical parameter ranges associated with 90% of orally active drugs that have
achieved phase II clinical status. See: Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. "Experimental and
Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings."
Adv. Drug Delivery Rev. 2001, 46, 3-26.
2
Wenlock, M. C.; Austin, R. P.; Barton, P. Davis, A. M.; Lesson, P. D. "A Comparison of Physicochemical Property
Profiles of Development and Marketed Oral Drugs." J. Med. Chem. 2003, 46, 1250-1256.
sc88
 Drug Lipophilicity

 Drug lipophilicity affects multiple parameters and must be

carefully managed.

 Parameters affected by drug lipophilicity include:

 Aqueous solubility

 Permeability

 Metabolic stability

 Volume of distribution/tissue binding and clearance

 Toxicity
 Balancing SAR and SPR

 Medicinal chemists must carefully balance structure-activity relationships (SAR)

with structure-property relationships (SPR) when optimizing analogues
throughout the drug discovery process.

 SAR – changes made to a compound scaffold that affects the binding

affinity and potency (biological activity) of the compound.

 SPR – changes made to a compound scaffold that affects the

physicochemical properties of the compound. These changes can effect
ADME properties:

 Absorption

 Distribution

 Metabolism

 Exrcetion (Elimination)
 Pharmacophore and Auxophore

 The structural elements of a compound (atoms and functional groups) not directly
involved in binding/activity.

 Role of the auxophore may include serving as a scaffold to hold pharmacophoric

groups in a specific 3D orientation, contribute to specific physiochemical properties
that affect PK or simply occupy space.

 Changes to the auxophore generally do not affect pharmacodynamics but may affect
pharmacokinetics.

 The auxophore can potentially be used as a handle to modulate physicochemical

properties.
Improving Solubility: Add Polar Auxophore Groups
Kinase Inhibitors - Using a "Handle" to Modify Physicochemical Properties

N
H H
Br NH N N N NCH3
OCH3
N N O

N OCH3

N
PD 153035 (1994) Gleevec®

Poorly soluble Improved solubility, %F

F
t-Bu O
O N
Cl NH O N O
N N N
O N H H
N

N OCH3

CH3
Iressa® BIRB 796
Improved solubility, %F Improved solubility, %F
 ACE Inhibitors - Using a "Handle" to Modify Physicochemical Properties

Ph NH2 Ph

CH3 (CH2)4 CH3

SH N HO N EtO N
N N
CO2H H H
O O O CO2H O O CO2H

Captopril (po BA = 65% Lisinopril (25% - AT) Enalapril (41% - PD or AT?)

via Active Transport) Similar IC50's with and w/o benzo fusion

Ph Ph Ph
H
H
CH3 CH3
N EtO N O
EtO N N
N
H H CH3 P
O CO2H O O CO2H
O O O CO2H
H3C
Quinapril (38%) Trandolapril (75%) OCOCH2CH3

Fosinopril (36%)
~
 Improving Solubility: Lower LogP
Rationale:

 Adding polar groups increases polarity and decreases hydrophobic character.

 Decreased LogP can help improve solubility.
 Basic amines and carboxylic acids can be converted into salts.

N N
Cl
N S N
OH N
Cl N
N O N N
N N N

H Cl S NN OH NF
N
C
C O
F
Cl
Cl F
tPSA: 24.83 tPSA: 76.15
CLogP: 5.32753 CLogP: -0.44
F
Cl
Fluconazole
Tioconazole
Antifungal agent with poor Systemic antifungal agent
solubility - skin infections only improved blood solubility
 Improving Permeability: Reduce tPSA
Discovery ADME - Prediction of Intestinal Absorption of ETA Antagonists

OCH3

O
O R
CO2H

O
O

ETA permeability (cm/s)

R K i (nM) Ro5 PSAd Caco-2 F (%) - rat

CO2H (SB 209670) 0.43 - 126.8 2.1 x 10-6 4

CH2OH (SB 217242*) 1.1 - 103.8 57 x 10-6 66

*SB 217242 clinical trials for CHF

Stenberg, P. et al, Pharm. Res. 1999, 16, 1520-1526 sc91o

 Improving Permeability: Vary pKa

Rationale:

 Varying pKa alters percentage of drug which is ionized

 Alter pKa to obtain required ratio of ionised to unionized drug

Method:

 Vary alkyl substituents on amine nitrogens.

 Vary aryl substituents to influence aromatic amines or aromatic carboxylic acids.
 Improving Permeability: Vary pKa

N N

O N O N
N N
N N
H H
O vs O

H2N NH N NH2

amidine amino pyridine

Antithrombotic Decreased basicity

but too basic N locked into heterocycle
 Improving Metabolic Stability: Blocking Groups

Rationale:

 Used to increase chemical and metabolic stability

 Introduce bulky group as a shield
 Protects a susceptible functional group (e.g. ester) from hydrolysis
 Hinders attack by nucleophiles or enzymes

O O
H
HS N
N N
H H
O  tert-Butyl group serves as a steric shield.
 Blocks hydrolysis of terminal amide.
O N O

Antirheumatic agent D1927

Improving Metabolic Stability: Blocking Groups
Rationale:

 Metabolism of drugs usually occur at specific sites. Introduce groups at

a susceptible site to block the reaction.
 Increases metabolic stability and drug lifetime.

O O
O O
H O H O
H H H H
O O
CH3 metabolism blocked at this site
metabolism at this site

Megesterol acetate
 Improving Metabolic Stability: Blocking Groups
Rationale:

 Metabolism of drugs usually occur at specific sites. Introduce fluorine atoms at

a susceptible site to block the reaction.
 Increases metabolic stability and drug lifetime.
 The carbon-fluorine bond is very strong and not susceptible to CYP-mediated
oxidation.

F F
F F
H H
N N
N N
O O
N O F N O F
S S
O O
2 3
GlyT-1 IC50 = 23.2 nM GlyT-1 IC50 = 67.5 nM
GlyT-2 IC50 >75 M GlyT-2 IC50 >75 M
HLM* = 16% remaining @ 60 min HLM = 64% remaining @ 60 min
 Lead Optimization - Benefits of Fluorine
Why do many new small molecule drugs contain one or more F's?

- Increased chemical and metabolic stability (defer to later discussions)

• C-F bond is one of the strongest known
• Adjacent C-C bonds are also strengthened

- F substitution can modulate physicochemical properties; H → F leads to:

• Higher lipophilicity (generally)
• Decrease pKa of basic centers [CH3CH2NH2 (10.7) → CF3CH2NH2 (5.7)]
• Increase in van der Waals volume not proportional to MW
- CH3 (MW = 15; VW = 21.6 Å3) → CF3 (MW = 69; VW = 39.8 Å3)

- Fluorine's contribution to protein-ligand interactions:

• HBA: C-F···H-O and C-F···H-N interactions
frequently observed in crystal structures
• Dipole interactions are numerous (e.g., C-F···C=O)

- Efficient synthetic methods (e.g., DAST)

Purser, S.; et al. Chem. Soc. Rev. 2008, 37, 320.

Müller, K.; et al, Science 2007, 317, 1881.
 Incorporating Drug Metabolism Early in the Discovery Process
Strategies to Overcome Metabolism Problems
• Avoid metabolic "hotspots" (e.g., esters)
• Modify physicochemical properties
- Decrease logP to retard extraction into the liver
• Once metabolite profile is known, modify the molecule to retard metabolism
- Beware of metabolic switching!

Cl
P450
X X X X
H HO F HO
Cl
Retards Phase II
glucuronidation

de Groot, M. J. "Designing better drugs: predicting cytochrome P450 metabolism." Drug Disc. Today 2006, 11, 601.
Henderson, A.; Guzzo, P. "Metabolism-driven optimization of pharmacokinetics." Curr. Drug Disc. 2004, May, 17.
 Strategies to Overcome Metabolic Inactivation
SO2NHC(=O)NH(CH2)3CH3 SO2NHC(=O)NH(CH2)2CH3

CH3 Cl
Tolbutamide Chlorpropamide

O O

OCH2CH2NEt2 NHCH2CH2NEt2

NH2 NH2
Procaine Procainamide

O O
OH
OH
O O
H3C H H CH3 H
O H3C O

O O

Lovastatin (MevacorTM) Simvastatin (ZocorTM)

X X X X
H OH O OH
Nuc

RNH RNH RN RNH Nuc

P450 hydroxylation of arylamines can be retarded by X = EWG

 Metabolism-Directed Optimization of Merck Thrombin Inhibitors
Burgey, C. S. et al, J. Med. Chem., 2003, 46, 461-473.

CH3 Oxid.
N O
N Conjugation
N N
H H
O
Oxid. H3C N NH2
K i = 0.8 nM
• di-F and 2-pyr   in K i • Remove NH2  350-fold  in K i
• 2-pyr   logP and  sol. • Of unsubt. analogues, 2-pyr best

CH3 CH3
N O N O
N N N
N N N N N
H H H H
F F O O
N NH2 K i = 390 nM
K i = 0.042 nM

Additive SAR observed CH3

 Potency by adding L.H. piece
N O
N N
N N N
H H
F F O
K i = 15 nM

3-F   metabolic stability (N to N O; CH2 to CHOH)

CH3
N O
K i = 4.2 nM
N N
t1/2 = 3.5 h N N N
H H
F F O
F
 Strategies to Enhance Metabolism

F3C N F3C N
N SO2NH2 N SO2NH2

Cl CH3

IC50 vs. COX-2 = 10 nM IC50 vs. COX-2 = 40 nM

t1/2 (rat) = 117 h t1/2 (rat) = 3.5 h

Penning, T. D. et al, J. Med. Chem. 1997, 40, 1347.