Structure-based design, synthesis, and evaluation of tetrahydrotriazolothiazepine derivatives as novel 11β-hydroxysteroid dehydrogenase type 1 inhibitors

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2026-01-01 Epub Date: 2025-09-24 DOI:10.1016/j.bmc.2025.118418

Yukinobu Numata , Toru Hasegawa , Makoto Mori , Tsuyoshi Shinozuka , Yuko Yamamoto , Masatoshi Honzumi , Chinami Kanayama , Atsushi Aoyagi , Manabu Abe , Yuka Ofune , Kanae Suzuki , Yuichiro Imamura , Chizuko Yahara , Wataru Obuchi , Ayako Moritomo , Mizuki Takahashi

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Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that converts cortisone to cortisol, and the therapeutic inhibition of this enzyme has attracted substantial attention for the treatment of various disorders including metabolic syndrome, cognitive decline, skin diseases, liver fibrosis, glaucoma, and osteoporosis. With the aim of developing a novel and potent 11β-HSD1 inhibitor, we designed and synthesized a series of tetrahydrotriazolothiazepine derivatives containing a sulfur atom in the seven-membered ring. An optimization study guided by structure-based drug design led to the discovery of compound 3f as a potent and orally bioavailable 11β-HSD1 inhibitor. The oral administration of 3f demonstrated good pharmacokinetic profiles and in vivo inhibition of 11β-HSD1 in mice and monkeys.

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新型11β-羟基类固醇脱氢酶1型抑制剂四氢三唑噻唑类衍生物的结构设计、合成和评价。

11β-羟基类固醇脱氢酶1型（11β-HSD1）是一种将可的松转化为皮质醇的酶，该酶的治疗抑制已引起广泛关注，用于治疗各种疾病，包括代谢综合征、认知能力下降、皮肤病、肝纤维化、青光眼和骨质疏松症。为了开发一种新型有效的11β-HSD1抑制剂，我们设计并合成了一系列在七元环上含有硫原子的四氢三唑噻唑类衍生物。在基于结构的药物设计指导下的优化研究导致化合物3f作为一种有效的口服生物可利用的11β-HSD1抑制剂被发现。口服3f在小鼠和猴子体内表现出良好的药代动力学特征和对11β-HSD1的体内抑制作用。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.