Novel imidazo[1,2-a]pyridine derivatives as potent ATX allosteric inhibitors: Design, synthesis and promising in vivo anti-fibrotic efficacy in mice lung model

Abstract

Aiming to develop novel allosteric autotaxin (ATX) inhibitors, hybrid strategy was utilized by assembling the benzyl carbamate fragment in PF-8380 onto the imidazo[1,2-a]pyridine skeleton of GLPG-1690. The piperazine moiety in GLPG-1690 was replaced with phenyl ring to enhance the π-π interactions with adjacent residues. In the light of FS-3 based ATX enzymatic assay, further structure-guided optimizations were implemented by exploring the substituents within the carbamate aromatic moiety and examining the effect of the 2-ethyl. Eventually, 13c bearing 1,3-benzodioxole and 2-hydroxyethyl piperazine group was identified as a powerful ATX inhibitor with an IC50 value of 2.7 nM. Subsequently, 13c was forwarded into an in vivo bleomycin-induced mice lung fibrosis model. In histopathological and immunohistochemical assays, 13c could typically alleviate the severity of fibrosis tissues and effectively reduce the deposition of fibrotic biomarker α-SMA. At a dose of 60 mg/kg, 13c was observed equivalent or even better potency than GLPG-1690 with a significant inhibition of the in vivo ATX activity. Except for the fundamental H-bond and π-π interactions, an extra H-bond between the 1,3-benzodioxole (O atom) and Phe306 offered great rationale in constraining the binding conformation of 13c. Finally, binding free energy calculation was conducted to assist in the efficient identification of allosteric ATX inhibitors.