MEDI 219 |
| Antagonists of the Calcitonin Gene-Related Peptide (CGRP) receptor represent a promising new approach for the treatment of migraine headache. CGRP is a vasodilator and neuropeptide involved in the pathogenesis of migraine headache. In a Phase II clinical study, intravenous infusion of the Boehringer-Ingelheim CGRP antagonist BIBN4096BS effectively relieved migraine pain and was well-tolerated. No cardiovascular or cerebrovascular effects were observed. Since CGRP receptor antagonists lack direct vasoconstrictor activity, this approach may offer advantages over current 5–HT1B/1D receptor agonists, where cardiovascular liabilities are a major perceived risk Ideally a CGRP receptor antagonist would be given orally. High throughput screening at Merck focused on discovering compounds with the potential to be developed into orally active CGRP receptor antagonists. A non-peptide lead structure with micromolar affinity for the CGRP receptor was identified. Although its high molecular weight and weak receptor affinity were disadvantages, several features of the molecule were attractive from the standpoint of lead optimization. The compound had a modular structure that linked a benzodiazepine core to a novel tetralin spirohydantoin. Structure activity studies identified key areas of the lead that contributed to receptor affinity, and optimization produced significant enhancements in potency. Pharmacokinetic studies focused on achieving oral bioavailability. Promising compounds were profiled in a novel pharmacodynamic model based on capsaicin-induced CGRP release in rhesus monkeys. Elements of design and optimization leading to MK-0974, an orally bioavailable CGRP receptor antagonist currently in clinical trials, will be discussed. |
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Beyond Tryptans
9:00 AM-11:30 AM, Tuesday, August 21, 2007 BCEC -- 210B, Oral
Division of Medicinal Chemistry |