Identification of Selective, Nonpeptidic Nitrile Inhibitors of Cathepsin S Using the Substrate Activity Screening Method

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• 作者：Andrew W. Patterson ; Warren J. L. Wood ; Michael Hornsby ; Scott Lesley ; Glen Spraggon ; Jonathan A. Ellman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：October 19, 2006
• 年：2006
• 卷：49
• 期：21
• 页码：6298 - 6307
• 全文大小：433K
• 年卷期：v.49,no.21(October 19, 2006)
• ISSN：1520-4804

文摘

The substrate activity screening method, a substrate-based fragment identification and optimization methodfor the development of enzyme inhibitors, was previously applied to cathepsin S to obtain low nanomolar1,4-disubstituted-1,2,3-triazole-based aldehyde inhibitors (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.;Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). Replacement of the metabolicallylabile aldehyde pharmacophore with the nitrile pharmacophore provided inhibitors with moderate potencyfor cathepsin S. The inhibitors showed good selectivity over cathepsins B and L but no selectivity overcathepsin K. X-ray structures of two crystal forms (1.5 and 1.9 Å) of a complex between cathepsin S anda triazole inhibitor incorporating a chloromethyl ketone pharmacophore guided the design of triazole substrateswith increased cleavage efficiency and selectivity for cathepsin S over cathepsins B, L, and K. Conversionof select substrates to nitrile inhibitors yielded a low molecular weight (414 Da) and potent (15 nM) cathepsinS inhibitor that showed >1000-fold selectivity over cathepsins B, L, and K.