468069-00-3Relevant articles and documents
Potent and selective nonpeptidic inhibitors of procollagen C-proteinase
Fish, Paul V.,Allan, Gillian A.,Bailey, Simon,Blagg, Julian,Butt, Richard,Collis, Michael G.,Greiling, Doris,James, Kim,Kendall, Jackie,McElroy, Andrew,McCleverty, Dawn,Reed, Charlotte,Webster, Robert,Whitlock, Gavin A.
, p. 3442 - 3456 (2008/02/11)
6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity 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 μM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 μg/cm2/h, which compares favorably with 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-scarring agent.
