Applying Pharmacology to New Drug Discovery
The System-independent quantification of molecular drug properties for prediction of therapeutic utility
Wednesday, June 15 | 8:30 am - 5:30 pm
Thursday, June 16 | 8:30 am - 12:30 pm

Over the past 6 six years, the primary cause of new drug candidate failures (50%) has been failure of therapeutic efficacy. Put another way, drug discovery programs do everything right, get the defined candidate molecule, only to have it fail in therapeutic trials. Among the most prevalent reasons proposed for this shortcoming is the lack of translation of in vitro and recombinant drug activity to therapeutic in vivo whole systems. Drug activity in complete systems can be characterized with the application of pharmacological principles which translate drug behaviors in various organs with molecular scales of affinity and efficacy.

Pharmacological techniques are unique in that they can convert descriptive data (what we see, potency, activity in a given system) to predictive data (molecular scales of activity that can be used to predict activity in all systems including the therapeutic one, i.e. affinity, efficacy). The predicted outcome of this process is a far lower failure rate as molecules are progressed toward clinical testing.

This course will describe pharmacological principles and procedures to quantify affinity, efficacy, biased signaling and allostery to better screen for new drugs and characterize drug candidates in lead optimization assays.

Course Outline:

Day 1, AM: (1) New Drug Discovery Infrastructure: Strategies- vs Target- vs Systems-Based, Discovery Teams, Target Selection; (2) Cellular Activation (agonism): Affinity and Efficacy, Potency, Biased Signaling, Selectivity, Screening for Agonists

Day 1, PM: (3) Antagonism: Orthosteric (competitive, non-competitive, hemi-equilibria), Partial Agonism, Screening for Antagonists; (4) Inverse Agonism; (5) Allosteric Modulation, PAMs, NAMs, Screening for Allosterics; (6) Candidate Selection: Real Time Kinetics and in vivo Target Coverage

Day 2, AM: Drug Development: (7) Pharmacokinetics: Druglike Character, in vivo Absorption, Distribution, Metabolism; (8) Excretion, in vivo PK, Non-Linear PK (9) Safety Pharmacology: Safety vs Toxicity Risk Benefit Analyses

Instructor: Terry Kenakin presently is a Professor of Pharmacology in the Dept of Pharmacology, University of North Carolina School of Medicine. The course is taught from the perspective of industrial drug discovery; Dr. Kenakin has worked in drug industry for 32 years (7 at Burroughs‐Wellcome, RTP, NC and 25 at GlaxoSmithKline, RTP. NC). He is Editor‐in‐Chief of the Journal of Receptors and Signal Transduction and Co‐Editor‐in‐Chief of Current Opinion in Pharmacology and is on numerous journal Editorial Boards. In addition, he has authored over 200 peer reviewed papers and reviews and has written 10 books on Pharmacology.

Course Material: Summary sheets, exercises with answers, relevant papers are included as well as a pdf of allslides. The course is based on the book A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery. 4th Edition, Elsevier/Academic Press, 2014. The table of contents of this book can be viewed at:
http://www.amazon.com/Pharmacology‐Primer‐Fourth‐Edition‐Techniques/dp/0124076637/ref=sr_1_1?ie=UTF8&qid=1404150228&sr=8‐1&keywords=kenakin#reader_0124076637.