Open AccessSuccessful Strategies for Mitigation of a Preclinical Signal for Phototoxicity in a DGAT1 Inhibitor
Author(s) -
Tyler Harrison,
Daniel Bauer,
Alina Berdichevsky,
Xin Chen,
Rohit Duvadie,
Benjamin Hoogheem,
Panos Hatsis,
Qian Liu,
Justin Mao,
Vasumathy Miduturu,
Erik C. Rocheford,
Frédéric Zécri,
Richard Zessis,
Rui Zheng,
Qingyu Zhu,
Ryan S. Streeper,
Sonika Patel
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00117
Subject(s) - phototoxicity , pharmacology , postprandial , medicine , population , chemistry , biochemistry , endocrinology , diabetes mellitus , environmental health , in vitro
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.