1. Identification of potent, highly constrained CGRP receptor antagonists.
- Author
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Stump CA, Bell IM, Bednar RA, Fay JF, Gallicchio SN, Hershey JC, Jelley R, Kreatsoulas C, Moore EL, Mosser SD, Quigley AG, Roller SA, Salvatore CA, Sharik SS, Theberge CR, Zartman CB, Kane SA, Graham SL, Selnick HG, Vacca JP, and Williams TM
- Subjects
- Animals, Biological Availability, Dogs, Drug Evaluation, Preclinical, Macaca mulatta, Quinolines chemistry, Quinolines pharmacokinetics, Rats, Calcitonin Gene-Related Peptide Receptor Antagonists, Quinolines pharmacology
- Abstract
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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