Send to

Choose Destination
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

Global Discovery Chemistry, Cardiovascular and Metabolism, and PK Sciences, Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.
Preclinical Safety, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.


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.

[Available on 2020-08-08]

Conflict of interest statement

The authors declare no competing financial interest.

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center