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ACS Med Chem Lett. 2019 Jun 20;10(8):1128-1133. doi: 10.1021/acsmedchemlett.9b00117. eCollection 2019 Aug 8.

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

Author information

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.

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.

PMID:
31413796
PMCID:
PMC6691483
[Available on 2020-08-08]
DOI:
10.1021/acsmedchemlett.9b00117

Conflict of interest statement

The authors declare no competing financial interest.

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