Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties
Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6- difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.
Richter, Hans G.F.,Benson,Bleicher,Blum,Chaput,Clemann,Feng,Gardes,Grether,Hartman,Kuhn,Martin,Plancher,Rudolph,Schuler,Taylor
p. 1134 - 1140
(2011/04/16)
Intermolecular C-H and Si-H insertion reactions with halodiazoacetates
Ethyl halodiazoacetates react with a range of substrates in regioselective rhodium(II)-catalysed C-H and Si-H insertion reactions giving α-halocarbonyl products in up to 82% yield. The halodiazoacetates are a novel class of diazo compounds that can undergo intermolecular carbenoid C-H insertion reactions, thus broadening the synthetic utility of such reactions. Georg Thieme Verlag Stuttgart.
Bonge, Hanne Therese,Hansen, Tore
experimental part
p. 91 - 96
(2009/06/24)
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