2. Academic Validation
  3. MK-8825: a potent and selective CGRP receptor antagonist with good oral activity in rats

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

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. ian_bell@merck.com
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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