发明新型 3-氨基哌啶-2-酮作为降钙素基因相关肽受体拮抗剂。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-02 DOI:10.1016/j.bmcl.2024.129944

Donnette D. Staas , Ian M. Bell , Christopher S. Burgey , James Z. Deng , Steven N. Gallicchio , John J. Lim , Daniel V. Paone , Craig M. Potteiger , Anthony W. Shaw , Heather Stevenson , Craig A. Stump , C. Blair Zartman , Eric L. Moore , Joseph G. Bruno , Scott D. Mosser , Rebecca B. White , Stefanie A. Kane , Christopher A. Salvatore , Samuel L. Graham , Theresa M. Williams , Mark E. Fraley

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引用次数: 0

摘要

在发现了意想不到的结构-活性观察结果后，我们发明了一系列基于 3-氨基哌啶-2-酮的新型降钙素基因相关肽（CGRP）受体拮抗剂。对结构-活性关系的初步探索产生了一种中等药效的先导结构（4）。通过一系列修改，包括环收缩和立体中心倒置，CGRP 受体的亲和力得到了惊人的改善。这些研究确定了化合物 23，这是一种结构新颖、药效强、可口服的 CGRP 受体拮抗剂。

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Invention of novel 3-aminopiperidin-2-ones as calcitonin gene-related peptide receptor antagonists

A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure–activity observations. Initial exploration of the structure–activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.