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

Authors :
Samuel L. Graham
Christine Fandozzi
Eric L. Moore
Donnette D. Staas
Ian M. Bell
Nova Sain
Joseph G. Bruno
Steven N. Gallicchio
Harold G. Selnick
Christopher A. Salvatore
Mark O. Urban
Rebecca B. White
Matthew M. Zrada
Amy Calamari
C. Blair Zartman
Amanda L. Kemmerer
Joseph P. Vacca
Stefanie A. Kane
Craig A. Stump
Scott D. Mosser
Source :
Bioorganic & Medicinal Chemistry Letters. 22:3941-3945
Publication Year :
2012
Publisher :
Elsevier BV, 2012.

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.

Details

ISSN :
0960894X
Volume :
22
Database :
OpenAIRE
Journal :
Bioorganic & Medicinal Chemistry Letters
Accession number :
edsair.doi.dedup.....e62e622cb95d0ea053c8a538444e4e67
Full Text :
https://doi.org/10.1016/j.bmcl.2012.04.105