MK-8825: a potent and selective CGRP receptor antagonist with good oral activity in rats

  • Bioorg Med Chem Lett. 2012 Jun 15;22(12):3941-5. doi: 10.1016/j.bmcl.2012.04.105.
Ian M Bell  1 ,  Craig A Stump ,  Steven N Gallicchio ,  Donnette D Staas ,  C Blair Zartman ,  Eric L Moore ,  Nova Sain ,  Mark Urban ,  Joseph G Bruno ,  Amy Calamari ,  Amanda L Kemmerer ,  Scott D Mosser ,  Christine Fandozzi ,  Rebecca B White ,  Matthew M Zrada ,  Harold G Selnick ,  Samuel L Graham ,  Joseph P Vacca ,  Stefanie A Kane ,  Christopher A Salvatore
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. [email protected]
PMID: 22607672 DOI: 10.1016/j.bmcl.2012.04.105
Abstract

Rational modification of the clinically tested CGRP Receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP Receptor blockade in vivo.

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