Advances in Pharmaceutical Research:
From Lead Discovery to Drug Manufacturing- Spring 2003
Syllabus Schedule Links Course Homepage
S. David Kimball, Ph.D. Vice President of Medicinal Chemistry
S. David Kimball, Ph.D. has been the Vice President of Medicinal Chemistry at Lexicon since August 2002 and served as the Senior Director of Medicinal Chemistry from August 2001 to August 2002. Before joining Lexicon, Dr. Kimball spent 19 years at the Bristol-Myers Squibb Pharmaceutical Research Institute, most recently as Research Fellow in the Division of Medicinal Chemistry, Princeton, New Jersey. During his tenure at the Institute, Dr. Kimball led several significant drug discovery and development research efforts, involving molecular targets in oncology, serine protease inhibitors of blood coagulation and ion channel modulators for the treatment of hypertension and angina. Dr. Kimball has been an Associate Member of the Graduate Faculty at Rutgers University School of Pharmacy since 1989. Dr. Kimball earned a Ph.D. in Organic Chemistry/Chemical Biology from the State University of New York at Stony Brook.
References:
A Comparison of Physiochemical Property Profiles of Development and Marketed Oral Drugs Wenlock, M. C.; Austin, R. P.; Barton, P.; Davis, A. M.; Leeson, P. D.; J. Med. Chem.; (Article); 2003; 46(7); 1250-1256.
The Hallmarks of Cancer Douglas Hanahan and Robert A. Weinberg; Cell, Vol. 100, 57-70, January, 2000
Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2: Synthesis, X-ray Crystallographic Analysis, and Biological Activities Kyoung Soon Kim, S. David Kimball, ... J. Med. Chem.; (Article); 2002; 45(18); 3905-3927.
Lipinski values ...
The "Lipinski Rule of Five" is called thus because the cutoffs for each of four parameters are all close to five or a multiple of five.
Quoting from Christopher A. Lipinski ... "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings":
"In the USAN set we found that the sum of Ns and Os in the molecular formula was greater than 10 in 12% of the compounds. Eleven percent of compounds had a MWT of over 500. Ten percent of compounds had a CLogP larger than 5 (or an MLogP larger than 4.15) and in 8% of compounds the sum of OHs and NHs in the chemical structure was larger than 5.
The Lipinski "Rule of Five" states that compounds are likely to have good absorption and permeation in biological systems and are more likely to be successful drug candidates if they meet the following criteria:
*five or fewer hydrogen-bond donors
*ten or fewer hydrogen-bond acceptors
*molecular weight less than or equal to 500
*calculated logP less than or equal to 5
Compound classes that are substrates for biological transporters are exceptions to the rule.
If two parameters are out of range, a "poor absorption or permeability is possible" alert is a very visible educational tool for the chemist and serves as a tracking tool for the research organization.