2019
DOI: 10.1021/acsmedchemlett.9b00117
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Successful Strategies for Mitigation of a Preclinical Signal for Phototoxicity in a DGAT1 Inhibitor

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… Show more

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Cited by 5 publications
(11 citation statements)
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“…Importantly, before employing in silico tools in a wider context, e.g., beyond the initial chemical context or even as a decision point in a general phototoxicity screening flowchart, it remains paramount to understand the overall performance in this wider chemical Figure 6. Structure alerts for phototoxicity: chlorpromazine, 43 methoxsalen, 44 hydrochlorothiazide, 45,46 triflusal, 47 lomefloxacin, 48 tetracycline, 49,50 fenofibrate, 51 extended aromatic hydrocarbons, 52 naproxen, 53 chlordiazepoxide, 54 voriconazole, 55 pradigastat, 56 atorvastatin, 57 and flutamide. 58 space.…”
Section: Phototoxicity�convention and Recent Advancesmentioning
confidence: 99%
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“…Importantly, before employing in silico tools in a wider context, e.g., beyond the initial chemical context or even as a decision point in a general phototoxicity screening flowchart, it remains paramount to understand the overall performance in this wider chemical Figure 6. Structure alerts for phototoxicity: chlorpromazine, 43 methoxsalen, 44 hydrochlorothiazide, 45,46 triflusal, 47 lomefloxacin, 48 tetracycline, 49,50 fenofibrate, 51 extended aromatic hydrocarbons, 52 naproxen, 53 chlordiazepoxide, 54 voriconazole, 55 pradigastat, 56 atorvastatin, 57 and flutamide. 58 space.…”
Section: Phototoxicity�convention and Recent Advancesmentioning
confidence: 99%
“…Harrison et al from Novartis hypothesized a putative diarylamine photocyclization to a carbazole photobyproduct, precedented by compounds like diclofenac, as a possible photodecomposition pathway. 56 The team sought modifications toward blocking such a process and eventually identified two successful solutions, as illustrated in Figure 23, by either removing ortho CH bonds via replacement of the terminal trifluoromethyl-pyridine with an oxadiazole (exemplified by compound 41) or inserting an amide linker to further isolate the two rings of the diaryl amine moiety (exemplified by compound 42). Both modifications completely abrogated the phototoxicity signal upon testing in the in vitro 3T3 NRU PT (PIF = 1) and offer potential mitigation strategies for phototoxic molecules containing a diaryl amine substructure.…”
Section: Photodecomposition or Reactive Photoproductsmentioning
confidence: 99%
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“…Pharmaceutical companies, including AstraZeneca (1) 12 , Novartis (2) 13 , Pfizer (3) 14 , and Abbott (4) 15 , and Hoffmann-La Roche (5) 16 are developing selective DGAT-1 inhibitors, whose structures are described in Figure 1. Other novel DGAT1 inhibitors have also been reported [17][18][19] .…”
Section: Introductionmentioning
confidence: 99%