Fragment-Based Discovery of an Oral Calcitonin Gene-Related Peptide Receptor Antagonist for the Treatment of Migraine.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-07-03 DOI:10.1021/acs.jmedchem.5c01127

Naohide Morita,Noritaka Furuya,Takaki Momose,Atsushi Kondo,Takehiro Ishikawa,Isao Wanajo,Michiyo Nishikawa,Motoyasu Ozawa,Masaoki Kajino,Hiroshi Harada,Akane Matsuzawa,Akihiro Tsuchioka,Hidemasa Hikawa,Isao Azumaya

引用次数: 0

Abstract

Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of migraine. In this study, we performed surface plasmon resonance-based fragment screening to identify various site binders and estimated their binding modes based on surface plasmon resonance and nuclear magnetic resonance studies using mutated CGRP receptors. Two fragment hits were merged and optimized to create compound 15, which showed good oral bioavailability in rats, attractive preclinical properties overall, and robust activity in a primate model of CGRP-induced facial blood flow.

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基于片段的口服降钙素基因相关肽受体拮抗剂治疗偏头痛的发现。

降钙素基因相关肽（CGRP）受体拮抗剂已证明在治疗偏头痛的临床疗效。在这项研究中，我们进行了基于表面等离子体共振的片段筛选，以识别各种位点结合物，并基于表面等离子体共振和使用突变CGRP受体的核磁共振研究估计了它们的结合模式。两个片段被合并并优化得到化合物15，该化合物在大鼠中具有良好的口服生物利用度，总体上具有吸引人的临床前特性，并且在cgrp诱导的灵长类动物面部血流模型中具有强大的活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.