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

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 μM. 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.