The discovery of highly potent CGRP receptor antagonists

  • Bioorg Med Chem Lett. 2009 Jan 1;19(1):214-7. doi: 10.1016/j.bmcl.2008.10.106.
Craig A Stump  1 ,  Ian M Bell ,  Rodney A Bednar ,  Joseph G Bruno ,  John F Fay ,  Steven N Gallicchio ,  Victor K Johnston ,  Eric L Moore ,  Scott D Mosser ,  Amy G Quigley ,  Christopher A Salvatore ,  Cory R Theberge ,  C Blair Zartman ,  Xu-Fang Zhang ,  Stefanie A Kane ,  Samuel L Graham ,  Joseph P Vacca ,  Theresa M Williams
Affiliations
  • 1. Department of Medicinal Chemistry, Merck & Co, Inc, West Point, PA 19486, USA. [email protected]
PMID: 19010673 DOI: 10.1016/j.bmcl.2008.10.106
Abstract

Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP Receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.

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