De novo design of novel and selective T-type calcium channel blockers

COMP 314

Daniel L. Cheney, cheneyd@bms.com1, Jon J. Hangeland, jon.hangeland@bms.com2, Todd J. Friends, todd.friends@bms.com2, and Paul C. Levesque, paul.levesque@bms.com3. (1) Computer-Assisted Drug Design, Bristol-Myers Squibb Company, P.O Box 5400, Princeton, NJ 08543-4000, (2) Cardiovascular Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 5400, Princeton, NJ 08543, (3) Cardiovascular Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, Princeton, NJ 08543-4000
Hypertension and angina pectoris afflict an estimated 200 million people in North America and Europe. Current therapies are limited to L-type calcium channel blockers which produce undesirable, mechanism-based side effects, such as edema and organ damage. An increasing body of evidence suggests that selective T-type calcium channel blockers may be clinically efficacious with significantly fewer side-effects. In this study, we describe the de novo design of novel, selective, and synthetically accessible T-type calcium channel blockers. Initial “idea structures” are generated by the program Sprout using a pharmacophore model derived from ComFA, small molecule crystal data, and high quality quantum mechanical conformational energy surfaces. Raw output structures were iteratively evolved into plausible, drug-like chemotypes, representatives of which were synthesized and found to exhibit moderate to high potency in in-vitro assays.
 

General Oral - Drug Discovery
8:10 AM-12:30 PM, Thursday, 17 March 2005 Convention Center -- Room 7A, Oral

Division of Computers in Chemistry

The 229th ACS National Meeting, in San Diego, CA, March 13-17, 2005