Publications by authors named "Timothy A Cernak"

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.

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Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.

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We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A2A receptor, no ACAT1 off-target activity at 10 μM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets.

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Diels-Alder cycloadditions of dehydroalanine derivatives with cyclopentadiene, applicable to the synthesis of palau'amine, were investigated experimentally and using DFT computations at the B3LYP/6-31G* level of theory. Oxazolone and thiohydantoin dienophiles were found to be significantly more reactive than hydantoins or dehydroalanine methyl esters. The increased reactivity of the thiohydantoins relative to hydantoins is attributed to increased conjugation of nitrogen lone pairs into the thiocarbonyl group.

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