Identification of a Chemical Probe for BLT2 Activation by Scaffold Hopping

The leukotriene B4 receptor 2 (BLT2) is a G-protein coupled receptor, which is endogenously activated by 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). BLT2 is gaining attention as a potential therapeutic target involved in various pathologies including diabetic wound healing, ophthalmic diseases, and colitis. However, validation of BLT2 as drug target requires chemical probes and pharmacological tools which will allow for application in vivo. In this work, we present the discovery of a novel chemical probe T-10430 for BLT2 agonism following a scaffold-hopping approach. T-10430 exhibits high potency, good selectivity profile, promising physicochemical and PK properties and can potentially serve as orally applicable pharmacological tool for validation of BLT2 as drug target. Using T-10430, we demonstrate the beneficial effect of BLT2 activation in mouse model of psoriasis.