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

  • ACS Med Chem Lett. 2019 Jun 20;10(8):1128-1133. doi: 10.1021/acsmedchemlett.9b00117.
Tyler J Harrison  1 ,  Daniel Bauer  2 ,  Alina Berdichevsky  1 ,  Xin Chen  1 ,  Rohit Duvadie  1 ,  Benjamin Hoogheem  1 ,  Panos Hatsis  1 ,  Qian Liu  1 ,  Justin Mao  1 ,  Vasumathy Miduturu  1 ,  Erik Rocheford  1 ,  Frederic Zecri  1 ,  Richard Zessis  1 ,  Rui Zheng  1 ,  Qingming Zhu  1 ,  Ryan Streeper  1 ,  Sejal J Patel  1
Affiliations
  • 1. Global Discovery Chemistry, Cardiovascular and Metabolism, and PK Sciences, Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.
  • 2. Preclinical Safety, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
PMID: 31413796 DOI: 10.1021/acsmedchemlett.9b00117
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.