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（R）-N-（3-（7-甲基-1H-吲唑-5-基）-1-（4-（1-甲基哌啶-4-基）-1-氧代丙-2-基）-4-（2-氧代-1,2-二氢喹啉-3-基）哌啶-1-甲酰胺（BMS-742413）的发现：一种通过鼻内给药治疗偏头痛的强效人降钙素基因相关肽拮抗剂，具有优越的安全性。

Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): a potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery.

机构信息

Department of Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA.

出版信息

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3157-61. doi: 10.1016/j.bmcl.2013.04.012. Epub 2013 Apr 12.

DOI:10.1016/j.bmcl.2013.04.012
PMID:23632269
Abstract

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow.

摘要

降钙素基因相关肽（CGRP）受体拮抗剂已被证明是有效的偏头痛发作治疗药物，没有与曲坦类药物相关的心血管副作用。本文报道了一种高效的 CGRP 受体拮抗剂 BMS-742413 的发现，该化合物有可能通过鼻内给药实现快速起效。该化合物具有出色的水溶性、氧化稳定性和毒理学特性。BMS-742413 在兔体内具有良好的鼻内生物利用度，并表现出对狨猴面部血流中 CGRP 诱导增加的强烈、剂量依赖性抑制作用。

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