1. MK-8825: A potent and selective CGRP receptor antagonist with good oral activity in rats
- Author
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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, and Scott D. Mosser
- Subjects
medicine.medical_specialty ,Pyridines ,Migraine Disorders ,Clinical Biochemistry ,Administration, Oral ,Biological Availability ,Pharmaceutical Science ,Calcitonin gene-related peptide ,Pharmacology ,Biochemistry ,Mice ,chemistry.chemical_compound ,Dogs ,Species Specificity ,Calcitonin Gene-Related Peptide Receptor Antagonists ,In vivo ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,Spiro Compounds ,Receptor ,Molecular Biology ,Analgesics ,Chemistry ,Organic Chemistry ,Antagonist ,Macaca mulatta ,Rats ,Blockade ,Disease Models, Animal ,Endocrinology ,Pharmacodynamics ,Molecular Medicine ,Acetamide ,Receptors, Calcitonin Gene-Related Peptide - 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.
- Published
- 2012
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