Structure-based drug design to overcome species differences in kallikrein 7 inhibition of 1,3,6-trisubstituted 1,4-diazepan-7-ones

Publication date: Available online 26 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Hidenobu Murafuji, Hajime Sugawara, Megumi Goto, Yoshiaki Oyama, Hiroki Sakai, Seiichi Imajo, Toshiyuki Tomoo, Tsuyoshi Muto
A series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were prepared as kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Previously reported compounds 1–3 were potent human KLK7 inhibitors; however, they did not exhibit inhibitory activity against mouse KLK7. Comparison of the human and mouse KLK7 structures reveals the cause of this species differences; therefore, compounds that could inhibit both KLK7s were designed, synthesized, and evaluated. Through this structure-based drug design, compound 22g was identified as an inhibitor against human and mouse KLK7, and only one of the enantiomers, (–)-22g, exhibited potent inhibitory activity. Furthermore, the crystal structure of mouse KLK7 complexed with 22g enabled the elucidation of structure-activity relationships and justified 22g as a valuable compound to overcome the species differences.

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