Murafuji Hidenobu, Sakai Hiroki, Goto Megumi, Imajo Seiichi, Sugawara Hajime, Muto Tsuyoshi
Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Bioorg Med Chem Lett. 2017 Dec 1;27(23):5272-5276. doi: 10.1016/j.bmcl.2017.10.030. Epub 2017 Oct 17.
Compound 1, composed of a 1,3,6-trisubstituted 1,4-diazepane-7-one, was discovered as a novel human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme, SCCE) inhibitor, and its derivatives were synthesized and evaluated. Structure-activity relationship studies of the amidoxime unit and benzoic acid part of this new scaffold led to the identification of 25 and 34, which were more potent than the hit compound, 1. The X-ray co-crystal structure of compound 25 and human KLK7 revealed the characteristic interactions and enabled explanations of the structure-activity relationship.
化合物1由1,3,6-三取代的1,4-二氮杂环庚烷-7-酮组成，被发现是一种新型的人组织激肽释放酶7（KLK7，角质层胰凝乳蛋白酶，SCCE）抑制剂，并对其衍生物进行了合成和评估。对该新骨架的偕胺肟单元和苯甲酸部分进行构效关系研究，确定了化合物25和34，它们比先导化合物1更具活性。化合物25与人KLK7的X射线共晶体结构揭示了其特征性相互作用，并能够解释构效关系。
