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 of an amide or suitable heterocyclic function. This strategy led to the development of two secondgeneration 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.

Phototoxicity─Medicinal Chemistry Strategies for Risk Mitigation in Drug Discovery

“…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.…”

“…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.…”

“…Importantly, before 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 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 space.…”

“…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 ■ STRATEGY 5: CONSIDERATION OF…”

Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors

“…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] .…”