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Autotaxin (ATX) is the dominant catalytic enzyme accounting for the lipid mediator lysophosphatidic acid (LPA) through hydrolysis of lysophosphatidylcholine (LPC). There is great interest in developing non-acidic ATX inhibitors with specific binding mode to serve as potential in vivo effective therapeutic tools. Herein, dating from an HTS product Indole-1(740 nM), a dedicated optimization campaign was implemented through derivatizing the -COOH group to versatile linkers that well bridged the indole skeleton and the hydrophobic pocket binding groups. Ultimately, it was established that the coexistence of carbamate linker and a -OH group containing amines could generally furnish excellent indole based ATX inhibitors with even below 1 nM in vitro activities. Two optimal entities were advanced to a bleomycin induced mice pulmonary fibrosis model which exerted promising efficacy in alleviating the damaged lung texture caused by bleomycin exposure. The novel carbamate-containing indole based ATX inhibitors with concrete binding mode may contribute to the identification of potential therapeutic agents to intervene the fibrotic diseases.
PMID: 32479084 [PubMed - as supplied by publisher]