Successful Strategies for Mitigation of a Preclinical Signal for Phototoxicity in a DGAT1 Inhibitor.

Basic Information

ID: ALA4304790

Journal: ACS Med Chem Lett

Title: Successful Strategies for Mitigation of a Preclinical Signal for Phototoxicity in a DGAT1 Inhibitor.

Authors: Harrison TJ, Bauer D, Berdichevsky A, Chen X, Duvadie R, Hoogheem B, Hatsis P, Liu Q, Mao J, Miduturu V, Rocheford E, Zecri F, Zessis R, Zheng R, Zhu Q, Streeper R, Patel SJ.

Abstract: 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.

CiteXplore: 31413796

DOI: 10.1021/acsmedchemlett.9b00117

Patent ID: ┄