1. Drug-Like Properties: Optimizing Pharmacokinetics and Safety During Drug Discovery
Li Di and Edward H. Kerns
ACS Short Course

2. Introduction to Drug-Like Properties
Few research compounds will become drugs because they lack sufficient pharmacokinetics (PK) and safety
Medicinal chemists strive to:
Deliver drug to the therapeutic target in sufficient concentration and time (PK)
Eliminate toxicity at the efficacious dose (safety)
Bind drug productively to the therapeutic target
Produce therapeutic efficacy in vivo
This course increases success in selecting and optimizing clinical candidates for good PK and safety

3. 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

4. Med-Chem Literature Case Studies Structure Modification
Short Course Format
Property
Effects
Med-Chem Literature Case Studies
Property
Fundamentals
Chemist
Structure Modification
Strategies
Lead
- with Liabilities
Candidate
with Improved PK

5. Course Overview Solubility Metabolic stability Permeability
Transporters (efflux and uptake)
Blood-Brain barrier
Plasma protein binding
Lipophilicity
pKa
Plasma stability
In vivo barriers to drug exposure
Introduction to pharmacokinetics and toxicity
Diagnosing property liabilities
CYP Inhibition
hERG
Formulation for in vivo dosing
Group exercises
Q & A encouraged

6. Example: PERMEABILITY

7. Example: Permeability Fundamentals
Rate of compound flux through a lipid membrane barrier
When is permeability important ?
Absorption – Intestine (orally delivered drugs)
Organ barriers (e.g., BBB)
Cells – In vivo tissue with target
Cells – In vitro biological assay

8. 95% of commercial drugs are primarily absorbed by passive diffusion
Example: Permeation Fundamentals
Permeation Mechanisms: P
P: Passive Diffusion*** F
F: Facilitated Uptake
A: Active Uptake
(Transporters) A D
D: Paracellular E
E: Efflux (Transporters)
e.g., P-glycoprotein
Epithelial
Cell
95% of commercial drugs are primarily absorbed by passive diffusion

9. Example: Effects of Improved Permeability
Increased bioavailability
Improved cell assay results
Higher blood-brain barrier penetration
Targeting of drugs to specific tissues
Reduced clearance

10. Example: Permeability Assay – PAMPA
Acceptor
Buffer (pH 7.4)
Artificial Lipid Membrane
Drug in Buffer (25g/mL, pH 7.4)
Donor
Measure “Pe” (Effective Permeability) via Passive Diffusion
M. Kansy, J Med Chem (1998) 41, 1007

11. Structural Modifications to Improve Permeability
Examples:
Increase lipophilicity
Reduce molecular weight
Reduce rotatable bonds
Prodrug

12. Advantages of Quality Drug-Like Properties
Higher quality clinical candidates
Advantageous partnering opportunities
Candidates have lower failure risk
Reduced time lag to fix PK liabilities later
Faster & less expensive development
Higher patient compliance
Better discovery biology data

13. Instructors
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
Edward H. Kerns – Staff Scientist, NIH – NCATS
Over 30 years in drug discovery and development
Co-authors of a leading book: “Drug-like Properties: Concepts, Structure Design and Methods”
Presented course over 25 times in 6 years