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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.

Studies Directed Towards the Refinement of the Pancratistatin Cytotoxic Pharmacophore.-The preparation of the deoxy-analogue (VIIIb) of the anticancer/antiviral agent pancratistatin (VIIIa) containing functionality complementary to the minimum structural pharmacophore utilizing a Diels-Alder approach is described. Initial anticancer screening of the two deoxyanalogues (VIIIb) and (VIIIc) shows marginal activity for (VIIIc) and selective inhibition of certain tumor cell lines by (VIIIb), however, at a significantly lower level compared to the natural product (VIIIa). -(MCNULTY, JAMES; MAO, JUSTIN; GIBE, ROMELO; MO, RUOWEI; WOLF, SONJA; PETTIT, GEORGE R.; HERALD, DELBERT L.; BOYD, MICHAEL R.; Bioorg. Med. Chem. Lett. 11 (2001) 2, 169-172; Dep. Chem., Brock Univ., St. Catharines, Ont. L2S 3A1, Can.; EN)

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