کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1366064 | 981580 | 2007 | 4 صفحه PDF | دانلود رایگان |
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%).
A series of (3R)-amino-(6S)-phenyl caprolactams were identified as benzodiazepine replacements for an early lead structure 1. The syntheses and SAR studies leading to the discovery of 24 are described.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 17, Issue 17, 1 September 2007, Pages 4795–4798