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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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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 [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study., (Copyright © 2019. Published by Elsevier Ltd.)

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. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development.

An oxidative carbonylation reaction that generates acid chloride functionality has been developed. Furthermore, this aminochlorocarbonylation reaction has been merged with a catalytic Friedel-Crafts acylation to produce a highly efficient tandem multicatalytic synthesis of pyrrolidinyl ketones. Significant variation of the aromatic nucleophile and substrate are shown. Two examples of incorporation of this method in triple-catalytic sequences are also demonstrated.

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. beta-Substitution greatly decelerates the cycloadditions due to steric interactions in the transition states outweighing any electronic activation by chlorine. Hydantoins and thiohydantoins were found to be exo-selective, while the corresponding oxazolones and dehydroalanines were unselective.