1477524-05-2Relevant articles and documents
Successful strategies for mitigation of a preclinical signal for phototoxicity in a dgat1 inhibitor
Harrison, Tyler J.,Bauer, Daniel,Berdichevsky, Alina,Chen, Xin,Duvadie, Rohit,Hoogheem, Benjamin,Hatsis, Panos,Liu, Qian,Mao, Justin,Miduturu, Vasumathy,Rocheford, Erik,Zecri, Frederic,Zessis, Richard,Zheng, Rui,Zhu, Qingming,Streeper, Ryan,Patel, Sejal J.
, p. 1128 - 1133 (2019/08/27)
Diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor Pradigastat (1) was shown to be effective at decreasing postprandial triglyceride levels in a patient population with familial chylomicronemia syndrome (FCS). Although pradigastat does not cause photosensitization in humans at the high clinical dose of 40 mg, a positive signal was observed in preclinical models of phototoxicity. Herein, we describe a preclinical phototoxicity mitigation strategy for diarylamine containing molecules utilizing the introduction of an amide or suitable heterocyclic function. This strategy led to the development of two second-generation compounds with low risk of phototoxicity, disparate exposure profiles, and comparable efficacy to 1 in a rodent lipid bolus model for post-prandial plasma triglycerides.