吡啶并[2,3-d][1]苯并氮杂环庚酮衍生物的先导优化导致发现了一种强效、选择性和可口服的人甲状旁腺激素受体 1（hPTHR1）拮抗剂（DS69910557）。
Lead optimization of pyrido[2,3-d][1]benzazepin-6-one derivatives leading to the discovery of a potent, selective, and orally available human parathyroid hormone receptor 1 (hPTHR1) antagonist (DS69910557).
机构信息
End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
出版信息
Bioorg Med Chem. 2022 Jun 15;64:116763. doi: 10.1016/j.bmc.2022.116763. Epub 2022 Apr 22.
We report the discovery of a series of novel zwitterionic hPTHR1 antagonists. Optimization of lead compound 2 led to 4-[[1-[4-(2,9-dichloro-5,5-dimethyl-6-oxo-pyrido[2,3-d][1]benzazepin-7-yl)phenyl]-3-fluoro-azetidin-3-yl]methylamino]cyclohexanecarboxylic acid (19e, DS69910557), a compound with excellent potency and selectivity over activity at the human ether-a-go-go-related-gene (hERG) channel. Compound 19e demonstrated in vivo potency to decrease the plasma calcium concentration in rats upon oral administration. 2022 Elsevier Ltd. All rights reserved.
我们报告了一系列新型两性离子 hPTHR1 拮抗剂的发现。先导化合物 2 的优化导致了 4-[[1-[4-(2,9-二氯-5,5-二甲基-6-氧代吡啶并[2,3-d][1]苯并氮杂卓-7-基)苯基]-3-氟氮杂环丁烷-3-基]甲基氨基]环己烷羧酸（19e，DS69910557）的发现，这是一种化合物，在人 ether-a-go-go-related-gene（hERG）通道中具有优异的效力和选择性。化合物 19e 在口服给药时表现出体内效力，可降低大鼠血浆钙浓度。2022 年爱思唯尔有限公司版权所有。
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