Group IVA cytosolic phospholipase A2 (GIVA cPLA2, cPLA2α) is a key enzyme of the inflammatory cascade. Therefore, inhibitors of GIVA cPLA2 are considered as attractive treatment options in the management of inflammatory diseases. Although considerable efforts in the development of clinical usable inhibitors of GIVA cPLA2 have been made by researchers in industry and academy for a couple of decades, no such substance has been commercialized up to now. The conventional GIVA cPLA2 inhibitors showed significant potency for the inhibition of the enzyme, but they had problems of low bioavailability due to their long alkyl side chains or large hydrophobic substituents in the molecule. Based on the crystal structure of a hit compound from our compound library, we originally designed a new series of indole-based small molecular GIVA cPLA2 inhibitors, 3-(1-aryl-1H-indol-5-yl)propanoic acids, which don’t have such unprofitable characters in their structure. In this study, we summarize hit-to-lead optimization of our new inhibitors that demonstrate nanomolar inhibitory potency against this enzyme with good cellular activity. PK profiles and the oral efficacies in animal models for the selected inhibitors are also described. ASB14780, one of the selected inhibitors, showed good oral efficacy in asthma model using guinea pig, which means this new inhibitor is a very promising drug candidate for the treatment of respiratory diseases.

Discovery of a new indole-based group IVA cytosolic phospholipase A2 inhibitor as a promising drug candidate for treatment of respiratory diseases

249th National Meeting (2015)

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