| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 10588339 | Bioorganic & Medicinal Chemistry Letters | 2012 | 5 Pages |
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)-2â²-oxo-1â²,2â²,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3â²-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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Authors
Ian M. Bell, 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,