Why the study?
Although the DGAT1 inhibitor pradigastat does not cause photosensitization in humans, a positive signal was observed in preclinical models of phototoxicity.
Does structural modification of DGAT1 inhibitors reduce phototoxicity in preclinical models?
Does structural modification of DGAT1 inhibitors reduce phototoxicity in preclinical models?
Structural modifications to DGAT1 inhibitors can successfully mitigate preclinical phototoxicity while maintaining efficacy for triglyceride reduction.
No phototoxicity seen with pradigastat in FCS despite preclinical signals; leaves open validation of the diarylamine mitigation strategy.
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.
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Harrison et al. (2019) studied this question.
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