ADME and hERG in Medicinal Chemistry

Outline

Day 1: Introduction to ADME

ADME Made Simple
A colourful voyage through the digestive system outlining the
elements of ADMET, absorption, permeability, pgp, CYP's, phase 1&2,
enteropatic cycling, toxicity, renal excretion, glomerular filtration, oral
absorption, first pass.

Round Table Discussion
Route of administration. Detection of pharmacologically active
metabolites in drug discovery. Ames test.

Pharmacokinetics - Definitions and Assays
A useful, easy to follow yet comprehensive guide to elimination
(half-life, extraction ratio, clearance, AUC) Distribution (volume of
distribution, half-life) absorption (bioavailablilty, iv, po), and overview of
corresponding assays methodologies.

Making the correct Diagnosis - ADME and the Medicinal Chemist
A step by step guide to correctly diagnosing the perennial issues in
lead optimization for drug design.

Workshop: ADMET Issues - Solutions that Work
Making the diagnosis and abstracting working solutions to recurrent
ADME issues from a range of key medicinal chemistry papers. This
team exercise provides a range of quality ideas that have been
successfully applied in topical research projects taken from a broad
spectrum of pharmaceutical companies.

Roundup Session and Outstanding Questions.

Day 2: hERG - La Bête Noire

hERG - An Introduction
hERG and IKr, ECG, TDP, QTC. The hERG channel structure, in silico
models, site directed mutagenicty studies. Assay methodologies.
Regulatory issues, current issues.

The hERG 4 Commandments - Designing out hERG Activity
An up to date overview of the literature and summary of key
approaches employed by the major players in the field. Lecture
illustrated with numerous worked examples on designing out hERG
activity.

Round up Session
WORKSHOP - Strategies for Diluting out hERG
A productive group session aimed at working through real life projects
designing out hERG activity. The ‘hERG 4 Commandments' will be
evaluated in parallel and discussed.

Round up Session: Conclusions and Recommendations

Topics Covered in the Course

• Overview of the human digestive system and its relevance to ADME issues
• Diagnosing ADME issues in a medicinal chemistry programme
• Working solutions to ADME issues taken from the literature
• Introduction to all key pharmacokinetics terms and their associated assay methodologies
• Overview of hERG and its impact on the drug discovery process
• Up to date hERG ‘wisdom' on diluting out IKr activity from lead compounds