Author: Murafuji, Hidenobu ; Muto, Tsuyoshi ; Oyama, Yoshiaki ; Goto, Megumi ; Imajo, Seiichi ; Fujioka, Hiromichi ; Murai, Kenichi ; Sugawara, Hajime ; Miyazaki, Shuji ; Minamitsuji, Yutaka

A series of imidazolinylindole derivatives were discovered as novel kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Structure-activity relationship (SAR) studies led to the identification of potent human KLK7 inhibitors. By further modification of the benzenesulfonyl moiety to overcome species differences in inhibitory activity, potent inhibitors against both human and mouse KLK7 were identified. Furthermore, the complex structure of 25 with mouse KLK7 could explain the SAR and the cause of the species differences in inhibitory activity.

01 Jul 2018·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Murafuji, Hidenobu ; Goto, Megumi ; Sakai, Hiroki ; Tomoo, Toshiyuki ; Oyama, Yoshiaki ; Imajo, Seiichi ; Muto, Tsuyoshi ; Sugawara, Hajime

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.

01 Sep 2017·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

3D-quantitative structure–activity relationship and docking studies of coumarin derivatives as tissue kallikrein 7 inhibitors

Q3 · MEDICINE

Article

Author: Zheng, Xin ; Zheng, Jun ; He, Mengxi ; Tan, Xiao ; Liu, Sen ; Wang, Fangyu

AbstractObjectivesKallikrein 7 (KLK7) is a secreted serine protease that plays important roles in skin desquamation and tumour progression, which makes it an attracting drug target. To guide the design of KLK7 inhibitors, a series of coumarin-based inhibitors were used to perform 3D-quantitative structure–activity relationship analysis.Methods3D conformations of 37 inhibitors were generated and used to construct CoMFA and CoMSIA models. Then a complex model between the inhibitors and KLK7 was built with molecular docking.Key findingsWith the training set, the CoMFA and CoMSIA models achieved q2 values of 0.521 and 0.498, and r2 values of 0.942 and 0.983, respectively. With the testing set, the predicted r2 values were 0.663 and 0.669, respectively, for CoMFA and CoMSIA. 3D contour maps from these two models identified steric and hydrophobic interactions as the most important molecular features of these inhibitors. Furthermore, molecular docking study was performed to understand the binding modes between these compounds and KLK7, in which the critical steric and hydrophobic interactions between the inhibitors and KLK7 were confirmed.ConclusionsSteric and hydrophobic interactions are critical in the efficient binding of KLK7 inhibitors. Our analysis would provide a meaningful guideline for the rational design of novel KLK7 inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Dermatitis, Atopic	Preclinical	Japan	Asubio Pharma Co. Ltd.	23 Jul 2018

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