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Successful strategies for mitigation of a preclinical signal for phototoxicity in a dgat1 inhibitor

Harrison, Tyler and Bauer, Daniel and Berdichevsky, Alina and Chen, Xin and Duvadie, Rohit and Gilmore, Thomas and Hoogheem, Benjamin and Hatsis, Panagiotis and Liu, Qian and Mao, Justin and Rajaraman, Vasumathy and Rocheford, Erik and Zecri, Frederic and Zessis, Richard and Zheng, Rui and Streeper, Ryan and 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

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