5-Aryl-1,3,4-oxadiazol-2-ylthioalkanoic Acids: A Highly Potent New Class of Inhibitors of Rho/Myocardin-Related Transcription Factor (MRTF)/Serum Response Factor (SRF)-Mediated Gene Transcription as Potential Antifibrotic Agents for Scleroderma

被引：34

作者：

Kahl, Dylan J. ^{[1
]}

Hutchings, Kim M. ^{[1
]}

Lisabeth, Erika Mathes ^{[5
]}

Haak, Andrew J. ^{[5
]}

Leipprandt, Jeffrey R. ^{[5
]}

Dexheimer, Thomas ^{[5
]}

Khanna, Dinesh ^{[3
,4
]}

Tsou, Pei-Suen ^{[3
,4
]}

Campbell, Phillip L. ^{[3
,4
]}

Fox, David A. ^{[3
,4
]}

Wen, Bo ^{[2
]}

Sun, Duxin ^{[2
]}

Bailie, Marc ^{[6
]}

Neubig, Richard R. ^{[5
]}

Larsen, Scott D. ^{[1
]}

机构：

[1] Univ Michigan, Coll Pharm, Vahlteich Med Chem Core, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Coll Pharm, UM Pharmcokinet Core, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Med Ctr, Dept Internal Med, Div Rheumatol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Med Ctr, Clin Autoimmun Ctr Excellence, Ann Arbor, MI 48109 USA

[5] Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA

[6] Michigan State Univ, Vivo Facil, E Lansing, MI 48824 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 09期

关键词：

MYOFIBROBLAST DIFFERENTIATION; MURINE MODEL; FIBROSIS; PATHWAY; TISSUE; CYTOSKELETON; CONTRACTION; DERIVATIVES; MECHANISMS; BLEOMYCIN;

D O I：

10.1021/acs.jmedchem.8b01772

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Through a phenotypic high-throughput screen using a serum response element luciferase promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated gene transcription with good potency (IC50 = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. The series nevertheless has no observable cytotoxicity up to 100 mu M. Ensuing pharmacokinetic optimization resulted in the development of two potent and orally bioavailable anti-fibrotic agents that were capable of dose-dependently reducing connective tissue growth factor gene expression in vitro as well as significantly reducing the development of bleomycin-induced dermal fibrosis in mice in vivo.

引用

页码：4350 / 4369

页数：20