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

Bioorganic & Medicinal Chemistry Letters
Theresa M WilliamsSamuel L Graham

Abstract

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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Citations

May 1, 2010·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Peter J Goadsby
Sep 8, 2010·Nature Reviews. Neurology·Tony W HoPeter J Goadsby
Mar 24, 2011·Future Medicinal Chemistry·John SpencerBabur Z Chowdhry
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Jul 10, 2007·Bioorganic & Medicinal Chemistry Letters·Anthony W ShawTheresa M Williams
Sep 22, 2018·Pain Management·Sameer JainStephen D Silberstein
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Jan 9, 2021·Signal Transduction and Targeted Therapy·Dehua YangMing-Wei Wang
Mar 2, 2021·Medicinal Research Reviews·Yohan MalkiNicolas Masurier

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