Design and synthesis of potent cgrp antagonists for migraine

MEDI 220

Prasad Chaturvedula1, Gene M. Dubowchik, gene.dubowchik@bms.com1, Andrew P Degan1, Xiaojun Han1, Charles M. Conway2, Deborah Cook2, Carl Davis3, Rex Denton4, Robert Macci5, Neil R Mathias6, Sokhom Pin2, Laura Signor2, George Thalody2, Richard Schartman5, Kimberly A Widmann7, Cen Xu2, and John E. Macor1. (1) Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, (2) Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, (3) Metabolism and Pharmacokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, (4) Discovery Toxicology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, (5) Pharmaceutics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, (6) Pharmaceutical Development, Bristol-Myers Squibb, One Squibb Drive, P.O. Box 191, New Brunswick, NJ 08903, (7) Bioanalytical Research, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492
Calcitonin Gene Related Peptide (CGRP), a naturally occurring 37 amino-acid peptide, has been implicated in the pathogenesis of migraine. Multiple lines of clinical evidence point to a role for CGRP in migraine. Treatment with a CGRP receptor antagonist would alleviate migraine by returning dilated intracranial arteries to normal without the liabilities of active vasoconstriction associated with triptans. Our medicinal chemistry effort has focused on the identification of potent CGRP antagonists with systemic bioavailability and potential for rapid onset of action. We will describe the design and synthesis of novel amino acids and GPCR privileged structures leading to potent CGRP antagonists with excellent aqueous solubility. The compounds display good systemic bioavailability and show dose-dependent activity in a validated in vivo marmoset migraine model.
 

Beyond Tryptans
9:00 AM-11:30 AM, Tuesday, August 21, 2007 BCEC -- 210B, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007