Drug-Like Properties: Optimizing Pharmacokinetics and

Safety During Drug Discovery

ACS Short Course

Li Di and Edward H. Kerns

Introduction to Drug-Like Properties

n Few research compounds will become drugs because

they lack sufficient pharmacokinetics (PK) and safety

n Medicinal chemists strive to:

1. Deliver drug to the therapeutic target in sufficient concentration and time (PK)

2. Eliminate toxicity at the efficacious dose (safety)

3. Bind drug productively to the therapeutic target

4. Produce therapeutic efficacy in vivo

n This course increases success in selecting and

optimizing clinical candidates for good PK and safety

There are Many Manifestations of Poor Properties During Drug Discovery

• Higher EC50 in cell assay than predicted from IC50

• Inadequate efficacy in animal model

• Poor brain penetration

• Low oral bioavailability

• Need a prodrug for absorption

• Inconsistent bioassay results

Short Course Format

Chemist

PropertyFundamentals

Lead- with

Liabilities

Candidate- with Improve

d PK

Structure Modification Strategies

PropertyEffects

Med-Chem Literature Case

Studies

Course Overviewn Solubilityn Metabolic stabilityn Permeabilityn Transporters (efflux and uptake)n Blood-Brain barriern Plasma protein bindingn Lipophilicityn pKan Plasma stabilityn In vivo barriers to drug exposuren Introduction to pharmacokinetics and toxicityn Diagnosing property liabilitiesn CYP Inhibitionn hERGn Formulation for in vivo dosingn Group exercisesn Q & A encouraged

Example:

PERMEABILITY

Example: Permeability Fundamentals

n Rate of compound flux through a lipid membrane barrier

n When is permeability important ?Absorption – Intestine (orally delivered drugs)Organ barriers (e.g., BBB)Cells – In vivo tissue with targetCells – In vitro biological assay

Permeation Mechanisms:

Example: Permeation Fundamentals

EpithelialCell

D

D: Paracellular

P

P: Passive Diffusion***

F

F: Facilitated Uptake

E

E: Efflux (Transporters)e.g., P-glycoprotein

A: Active Uptake (Transporters)

A

95% of commercial drugs are primarily absorbed by passive diffusion

Example: Effects of Improved Permeability

• Increased bioavailability

• Improved cell assay results

• Higher blood-brain barrier penetration

• Targeting of drugs to specific tissues

• Reduced clearance

Example: Permeability Assay – PAMPA

Artificial Lipid Membrane

Donor

Acceptor Buffer (pH 7.4)

Drug in Buffer (25g/mL, pH 7.4)

Measure “Pe” (Effective Permeability) via Passive Diffusion

M. Kansy, J Med Chem (1998) 41, 1007

Structural Modifications to Improve Permeability

Examples:n Increase lipophilicityn Reduce molecular weightn Reduce rotatable bonds n Prodrug

NH

HN

O

ONH

HN

O

O

Advantages of Quality Drug-Like Properties

n Higher quality clinical candidates

n Advantageous partnering opportunities

n Candidates have lower failure risk

n Reduced time lag to fix PK liabilities later

n Faster & less expensive development

n Higher patient compliance

n Better discovery biology data

n Dr. Li Di – Associate Research Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer Research

Over 20 years in drug discovery and development Over 120 research publications and invited lectures

n Edward H. Kerns – Staff Scientist, NIH – NCATS Over 30 years in drug discovery and development Over 120 research publications and invited lectures

Instructors

n Co-authors of a leading book: “Drug-like Properties: Concepts, Structure Design and Methods”

n Presented course over 25 times in 6 years