Successive structural optimization of Ziritaxestat culminates in the discovery of orally bioavailable and in vivo potent imidazothiadiazole derivative for treating ATX-driven diseases.

Herein, we communicate our medicinal chemistry campaign culminating in the discovery of imidazothiadiazole-based ATX inhibitor with oral bioavailability and potent in vivo efficacy. During our successive structural modification of Ziritaxestat, an ATX inhibitor advanced into phase III clinical trial, a total of 25 analogs have been designed and synthesized for improving its potency. Among them, 9 compounds exhibited single-digit nanomolar ATX inhibitory activity (IC = 2.54-9.01 nM), which was remarkably enhanced over Ziritaxestat (IC = 29.9 nM). In particular, compound 25, an imidazothiadiazole derivative that incorporated deuterated N-methyl for boosting metabolic stability, displayed an oral bioavailability of 27.1 %. In air pouch model of inflammation, it exerted superior in vivo efficacy to that of Ziritaxestat, as revealed by the more dramatic suppression of LPA secretion resulted from the treatment with 25. Moreover, 25 demonstrated promising therapeutic efficacy against bleomycin-induced systemic sclerosis in mice. Attributed to its attractive in vitro and in vivo performance in battling ATX-related diseases, 25 deserves further development as a potential candidate.