MGAT2
inhibition is a potential therapeutic approach for the treatment
of metabolic disorders. High-throughput screening of the BMS internal
compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs
mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry
route was developed to synthesize aryl dihydropyridinone analogs to
explore structure–activity relationship around this hit, leading
to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver
microsomal metabolism. After triaging out 21f due to
its inferior in vivo potency, pharmacokinetics, and
structure-based liabilities and tetrazole 28e due to
its inferior channel liability profile, 21s (BMS-963272)
was selected as the clinical candidate following demonstration of
on-target weight loss efficacy in the diet-induced obese mouse model
and an acceptable safety and tolerability profile in multiple preclinical
species.
A specific chromosomal aberration was observed in 14 of 15 avian lymphoblastoid cell lines transformed with Marek's disease herpesvirus. This aberration, designated dup(1p)(p22-p23), appeared as an extra G-positive band and interband on the short arm of one chromosome I homolog. Using fluorescent in situ hybridization, we identified amplified genomic DNA sequences in this region. This amplification involves sequences linked to an endogenous retrovirus locus and genes in the histone multigene family. This aberration was not observed in cells transformed by reticuloendotheliosis virus or by avian leukosis virus, nor has it been observed in untransformed chicken cells. The induction of the 1p+ chromosomal aberration may be an essential event in the transformation of lymphocytes by Marek's disease virus.
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