Potent and Selective Nonpeptidic Inhibitors of Procollagen C-Proteinase
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- 作者：Paul V. Fish ; Gillian A. Allan ; Simon Bailey ; Julian Blagg ; Richard Butt ; Michael G. Collis ; Doris Greiling ; Kim James ; Jackie Kendall ; Andrew McElroy ; Dawn McCleverty ; Charlotte Reed ; Robert Webster
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：July 26, 2007
- 年：2007
- 卷：50
- 期：15
- 页码：3442 - 3456
- 全文大小：396K
- 年卷期：v.50,no.15(July 26, 2007)
- ISSN：1520-4804
文摘
6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors ofprocollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discovera second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermaldelivery (TED) to intact skin. Further investigation of this template identified a number of potent PCPinhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzymeactivity when measured with a peptide substrate (Ki 8.7 nM) or with the endogenous substrate procollagen(IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 ± 2% at 10 
M and wasvery effective at penetrating human skin in vitro with a TED flux of 1.5 g/cm2/h, which compares favorablywith values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045)was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarringagent.
M and wasvery effective at penetrating human skin in vitro with a TED flux of 1.5 g/cm2/h, which compares favorablywith values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045)was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarringagent.