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Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead |
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| Authors: | Williams Theresa M Stump Craig A Nguyen Diem N Quigley Amy G Bell Ian M Gallicchio Steven N Zartman C Blair Wan Bang-Lin Penna Kimberly Della Kunapuli Priya Kane Stefanie A Koblan Ken S Mosser Scott D Rutledge Ruth Z Salvatore Christopher Fay John F Vacca Joseph P Graham Samuel L |
| Institution: | Department of Medicinal Chemistry Merck & Co., West Point, PA 19486, USA. theresa_williams@merck.com |
| 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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