Structure-based drug design of 1,3,6-trisubstituted 1,4-diazepan-7-ones as selective human kallikrein 7 inhibitors

被引：8
|
作者：
Murafuji, Hidenobu [1 ]
Sakai, Hiroki [1 ,2 ]
Goto, Megumi [1 ,2 ]
Oyama, Yoshiaki [1 ]
Imajo, Seiichi [1 ]
Sugawara, Hajime [1 ]
Tomoo, Toshiyuki [1 ]
Muto, Tsuyoshi [1 ]
机构：
[1] Asubio Pharma Co Ltd, Chuo Ku, 6-4-3 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan
[2] Daiichi Sankyo Co Ltd, Shinagawa R&D Ctr, Shinagawa Ku, 1-2-58 Hiromachi, Tokyo 1408710, Japan
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 08期
关键词：
Atopic dermatitis; Serine protease; Kallikrein; 7; inhibitor; 1,4-Diazepan-7-one; Structure-based drug design; EPIDERMAL BARRIER DYSFUNCTION; ATOPIC-DERMATITIS; STRATUM-CORNEUM; SERINE PROTEASES; DESQUAMATION; EXPRESSION; SKIN;
D O I：
10.1016/j.bmcl.2018.03.011
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A novel series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were investigated as human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Based on the X-ray co-crystal structure of compound 1 bound to human KLK7, the derivatives of this scaffold were designed, synthesized, and evaluated. Through structure-activity relationship studies focused on the side chain located in the prime site region of the enzyme, representative compounds 15, 33a, and 35a were identified as highly potent and selective inhibitors of human KLK7. (C) 2018 Elsevier Ltd. All rights reserved.
引用
收藏
页码：1371 / 1375
页数：5
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