Potent and selective nonpeptidic inhibitors of procollagen C-proteinase
Potent and selective nonpeptidic inhibitors of procollagen C-proteinase
复制标题
DOI：
10.1021/jm061010z
复制
发表时间：
2007-07-26
影响因子：
7.3
通讯作者：
Whitlock, Gavin A.
中科院分区：
文献类型：
--
作者：
Fish, Paul V.;Allan, Gillian A.;Whitlock, Gavin A.
先前公开了6-环己基-N-羟基-3-（1，2，4-恶二唑-5-基）己酰胺作为前胶原C-蛋白酶（PCP）的抑制剂，最终鉴定出酰胺1。我们的目标是发现第二种抑制剂，其对PCP具有改善的亲和力，并优化经表皮递送（TED）至完整皮肤的性质。对该模板的进一步研究鉴定了许多具有改善的TED通量的有效PCP抑制剂（IC 50值为2-6 nM）。当用肽底物（Ki 8.7 nM）或内源性底物前胶原（IC 50 3.4 nM）测量时，磺胺56具有出色的PCP酶活性，并且对参与伤口愈合的MMPs表现出出色的选择性（> 10000倍）。在纤维增生模型中，56在10 μ M时抑制不溶性胶原蛋白沉积76 +/- 2%，并且在体外渗透人体皮肤时非常有效，TED通量为1.5 μ g/cm（2）/h，这与已知在体内渗透皮肤良好的药剂的值相比是有利的。基于该特征，选择56（UK-421，045）作为局部应用的皮肤抗瘢痕形成剂进行进一步临床前评价的候选药物。
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 (K-i 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 mu M and was very effective at penetrating human skin in vitro with a TED flux of 1.5 mu g/cm(2)/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.