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

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.

Graphical abstractStructure 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 full-size imageDownload as PowerPoint slide