Design, synthesis and SAR of novel and selective T-type calcium channel antagonists containing a biaryl sulfonamide core

MEDI 105

Jon J. Hangeland, jon.hangeland@bms.com1, Todd J. Friends, todd.friends@bms.com1, Daniel L. Cheney, cheneyd@bms.com2, Paul C. Levesque, paul.levesque@bms.com3, Adam J. Rich, arich@brockport.edu3, Lucy Sun, lucy.sum@bms.com3, Terry R. Bridal3, Leonard P. Adam, leonard.adam@bms.com3, and Diane E. Normandin, diane.normandin@bms.com3. (1) Cardiovascular Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 5400, Princeton, NJ 08543, (2) Department of Macromolecular Structure, Bristol Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, (3) Cardiovascular Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, Princeton, NJ 08543-4000
Selective blockade of the T-type calcium channel has been shown to be an effective treatment for hypertension and stable angina, without the side effects common to L-type channel blockers such as increased heart rate and edema. Design of novel T-type channel blockers was carried out using an iterative design, synthesis, in vitro evaluation paradigm. Molecules were designed with the program SPROUT using constraints provided by a ComFA pharmacophore model. Scaffolds generated by SPROUT were evaluated based on frequency of occurrence and their ability to be translated into structures that were synthetically tractable. From this exercise, a novel series of potent and selective T-type channel antagonists were discovered.
 

Poster Session and Social Hour
6:00 PM-8:00 PM, Sunday, 13 March 2005 Convention Center -- Sails Pavilion, Poster

Division of Medicinal Chemistry

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