Author/Authors :
Anthony W. Shaw، نويسنده , , Daniel V. Paone، نويسنده , , Diem N. Nguyen، نويسنده , , Craig A. Stump، نويسنده , , Christopher S. Burgey، نويسنده , , Scott D. Mosser، نويسنده , , Christopher A. Salvatore، نويسنده , , Ruth Z. Rutledge، نويسنده , , Stefanie A. Kane، نويسنده , , Kenneth S. Koblan، نويسنده , , Samuel L. Graham، نويسنده , , Joeseph P. Vacca، نويسنده , , Theresa M. Williams، نويسنده ,
Abstract :
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Replacements for the benzodiazepine core of an earlier lead structure 1 including 5-, 6-, and 7-membered lactams were explored. Within the 7-membered ring scaffold, phenyl substitution at various positions afforded the potent (3R)-amino-(6S)-phenyl caprolactam template. The phenylimidazolinone privileged structure gave additional potency enhancements, as 24 showed good potency in both CGRP binding (Ki = 2 nM) and cAMP (IC50 = 4 nM) assays and was orally bioavailable in rats (27%).
Keywords :
CGRP , CGRP receptor antagonist , Migraine , Caprolactam
