Structural and PK-guided identification of indole-based non-acidic autotaxin (ATX) inhibitors exhibiting high in vivo anti-fibrosis efficacy in rodent model

In recent decades, pharmacological targeting of the autotaxin (ATX)/lysophosphatidic acid (LPA) axis accounted for excellent disease management benefits. Herein, to extend the scope of structure-activity relationships (SARs), fifteen indole-based carbamate derivatives (1–15) were prepared to evaluate the ATX inhibitory potency. Among them, compound 4 bearing morpholine moiety was identified as the optimal ATX inhibitor (0.41 nM), superior to the positive control GLPG1690 (2.90 nM). To resolve the intractable issue of poor pharmacokinetic (PK) property, urea moiety was introduced as a surrogate of carbamate which furnished compounds 16–30. The dedicated modification identified the diethanolamine entity 30 with satisfactory water solubility and PK profiles with a minimum sacrifice of ATX inhibition (2.17 nM). The most promising candidate 30 was evaluated for anti-fibrosis effect in a bleomycin challenged mice lung fibrosis model. Upon treatment with 30, the in vivo ATX activity in both lung homogenate and broncheoalveolar fluid (BALF) sample was significantly down-regulated. Furthermore, the gene expression of pro-fibrotic cytokines transforming growth factor-β (TGF-β), interleukin- 6 (IL-6) and tumor necrosis factor-α (TNF-α) in lung tissue was reduced to normal level. Collectively, the promising biological effects may advocate potential application of 30 in fibrosis relevant diseases. [Display omitted] •Thirty indole analogs bearing carbamate/urea as potent autotaxin (ATX) inhibitors.•SAR studies furnished the most powerful inhibitor 4 (0.41 nM) and 30 (2.17 nM).•30 exerted improved PK profile with minimum enzymatic sacrifice than that of 4.•30 presented encouraging in vivo effects in bleomycin induced mice fibrosis model.•30 inhibited in vivo ATX and the gene expression of pro-fibrotic factors.