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The Japanese proverb says "Fall seven times, get up, eight"

This is particularly true in the practice of drug discovery.  As I was preparing for this Friday's seminar, that we will give jointly with Apredica, at UCSF.  I had occasion to review an example of lead-optimization and nomination of a clinical candidate.  This series of three papers, that I choseto discuss as a case study, went from a discontinued clinical compound -to a novel NCE - to clinical candidate.

 ( see: series of papers by Mowbray, et al., Bioorganic & Medicinal Chemistry Letters, 2009 )

On paper, it sounded so easy...  If only they knew in advance, where they would end up.  From the starting point, to the candidate spanned hundreds of compounds, and many man-hours of synthetic and analytical effort.  

All this was done according to a plan that divided the molecule into three zones, for trial of various substituents.  [ Recall that Julius Caesar said that "All Gaul is divided into three parts" ]

LogP got worse, while half life in human liver microsomes got better.  Then the opposite occurred in the next wave.  then back again, as they "fell down" and "got up" many times, in a pitched battle of man vs nature.

In the end, they got it right.  Log P was superbly low.  Half life and predicted clearance were in a good range, and in vitro tox was clean.

( Please see our blog entry of January 26, 2010 on Lipinski's Rules, LogP and other Physicochemical properties that affect drug properties and activity. )

WE are particularly pleased to inaugurate our seminars at UCSF, the premier US institution of academic drug development.  As we noted in the March 9 Blog entry,  there is increasing interest in academic sources of drug discovery, as the models  for innovation, entrepreneurshipand the industry evolve  in the new decade.

Hear all about it this Friday, April 23, 2010, at 12:00 in 212 Byers Hall,  at the UCSF Mission Bay campus, San Francisco.

Medicinal Chemistry – The Roles of Chemistry in Drug Discovery(AsisChem- Emile Bellott)
and
Drug-like Properties -- Why early in vitro ADME is Important (Apredica - Bob Annand )