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Bioorg Med Chem Lett. 2006 May 15;16(10):2595-8. Epub 2006 Mar 9.

Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead.

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Department of Medicinal Chemistry Merck & Co., West Point, PA 19486, USA.


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 K(i)=44nM and IC(50)=38nM. Compound 7 was orally bioavailabile in rats and is a lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine.

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