کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1378848 | 982012 | 2006 | 4 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead](/preview/png/1378848.png)
High-throughput screening of the Merck sample collection identified benzodiazepinone tetralin-spirohydantoin 1 as a CGRP receptor antagonist with micromolar activity. Comparing the structure of 1 with those of earlier peptide-based antagonists such as BIBN 4096 BS, a key hydrogen bond donor–acceptor pharmacophore was hypothesized. Subsequent structure activity studies supported this hypothesis and led to benzodiazepinone piperidinyldihydroquinazolinone 7, CGRP receptor Ki = 44 nM and IC50 = 38 nM. Compound 7 was orally bioavailabile in rats and is a lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine.
Structure activity studies led to the non-peptide CGRP antagonist, 7 (Ki = 44 nM, IC50 = 38 nM), which was orally bioavailable in rats. Benzodiazepinone 7 is a promising new lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 16, Issue 10, 15 May 2006, Pages 2595–2598