Harrison, Tyler, Bauer, Daniel, Berdichevsky, Alina, Chen, Xin, Duvadie, Rohit, Gilmore, Thomas, Hoogheem, Benjamin, Hatsis, Panagiotis, Liu, Qian, Mao, Justin, Rajaraman, Vasumathy, Rocheford, Erik, Zecri, Frederic, Zessis, Richard, Zheng, Rui, Streeper, Ryan, Patel, Sejal and Zhu, Qingming (2019) Successful strategies for mitigation of a preclinical signal for phototoxicity in a dgat1 inhibitor. ACS Medicinal Chemistry Letters, 10 (8). pp. 1128-1133. ISSN 19485875

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.

Item Type:	Article
Keywords:	DGAT1 diacylglycerol acyltransferase inhibitor diaryl amines phototoxicity pradigastat triglycerides
Date Deposited:	27 May 2020 00:45
Last Modified:	27 May 2020 00:45
URI:	https://oak.novartis.com/id/eprint/39977