Discovery of MK-0974: A potent, orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist for the treatment of migraine

MEDI 20

Daniel V. Paone, daniel_paone@merck.com1, Anthony Shaw1, Diem Nguyen1, Chris Burgey, christopher_burgey@merck.com1, James Deng1, Craig Stump1, Amy Quigley1, Jane DeSolms1, Stefanie Kane2, Ken Koblan2, Rodney Bednar2, John Mallee2, Scott Mosser2, Chris Salvatore2, Daniel McMasters3, Jim Hershey4, Halea Corcoran4, Betsy Lyle4, Brad Wong5, Shane Roller5, Cindy Miller-Stein5, Janice Rowe5, Sean Yu5, Sam Graham1, Joseph Vacca1, and Theresa Williams1. (1) Department of Medicinal Chemistry, Merck Research Laboratories, WP14-2, 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486, (2) Pain Research, Merck Research Laboratories, WP14-2, 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486, (3) Molecular Systems, Merck Research Laboratories, WP14-2, 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486, (4) Molecular Endocrinology, Merck Research Laboratories, WP14-2, 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486, (5) Drug Metabolism, Merck Research Laboratories, WP14-2, 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486
Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide that is a potent vasodilator and has been implicated in the pathogenesis of migraine. Since CGRP receptor antagonists promote normalization of dilated blood vessels through a non-vasoconstrictive mechanism, this class of compounds could prove effective in the relief of migraine without the adverse cardiovascular effects that are sometimes associated with existing therapies. Our research program targeted non-peptide, small molecule CGRP receptor antagonists with favorable pharmacokinetic profiles that would result in the first oral drug in this class. Core truncation of a high-throughput screening lead followed by extensive SAR studies provided potent derivatives with improved oral bioavailabilities. Further refinement resulted in MK-0974, ultimately providing the optimal blend of potency and pharmacokinetic profiles. This compound showed efficacy in a capsaicin-induced dermal vasodilation pharmacodynamic assay in rhesus, and is currently in clinical trials for the treatment of acute migraine. The synthetic chemistry developed to access these compounds will also be described.
 

First Time Disclosure of Clinical Candidates
1:30 PM-5:30 PM, Sunday, March 25, 2007 McCormick Place Lakeside -- Room E353 A/B, Level 3, Oral

Division of Medicinal Chemistry

The 233rd ACS National Meeting, Chicago, IL, March 25-29, 2007