Three for three: De novo design of multiple novel chemotypes of T-type calcium channel blockers

COMP 148

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
An increasing body of evidence suggests that selective T-type calcium channel blockers may be clinically efficacious in the treatment of hypertension and angina pectoris while incurring significantly fewer side-effects than current therapies involving blockade of the L-type calcium channel. In this report, we describe the de novo design of novel, selective, and synthetically accessible T-type calcium channel blockers. Prototype molecules 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. Output structures were iteratively refined into drug-like chemotypes, representatives of which were synthesized and found to exhibit moderate to high potency in in-vitro assays.
 

Poster Session
6:00 PM-8:00 PM, Tuesday, 15 March 2005 Convention Center -- Sails Pavilion, Poster

Sci-Mix
6:00 PM-8:00 PM, Monday, 14 March 2005 Convention Center -- Sails Pavilion, Sci-Mix

Division of Computers in Chemistry

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