Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma
Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma
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DOI：
10.1016/j.bmcl.2017.02.070
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发表时间：
2017-04-15
影响因子：
2.7
通讯作者：
Larsen, Scott D.
中科院分区：
文献类型：
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作者：
Hutchings, Kim M.;Lisabeth, Erika M.;Larsen, Scott D.
我们最近报道了一种新型Rho介导的基因转录抑制剂（1，CCG-203971）的开发，当腹腔内给药时，该抑制剂在多种急性纤维化动物模型（包括硬皮病）中有效。然而，该铅的体内效力适中且药代动力学（PK）差，使得其不适合用于长期功效研究。因此，我们进行了系统的药物化学努力，以提高代谢稳定性和溶解度的1，导致在识别的两个类似物实现超过10倍的增加在小鼠中的血浆暴露。我们随后发现，这些类似物之一（8 f，CCG-232601）在以50 mg/kg口服给药时可以抑制小鼠中博来霉素诱导的皮肤纤维化的发展，该效果与我们先前在高4倍的IP剂量下观察到的效果相当。(C)2017爱思唯尔有限公司版权所有
We recently reported the development of a novel inhibitor of Rho-mediated gene transcription (1, CCG-203971) that is efficacious in multiple animal models of acute fibrosis, including scleroderma, when given intraperitoneally. The modest in vivo potency and poor pharmacokinetics (PK) of this lead, however, make it unsuitable for long term efficacy studies. We therefore undertook a systematic medicinal chemistry effort to improve both the metabolic stability and the solubility of 1, resulting in the identification of two analogs achieving over 10-fold increases in plasma exposures in mice. We subsequently showed that one of these analogs (8f, CCG-232601) could inhibit the development of bleomycin-induced dermal fibrosis in mice when administered orally at 50 mg/kg, an effect that was comparable to what we had observed earlier with 1 at a 4-fold higher IP dose. (C) 2017 Elsevier Ltd. All rights reserved.