ABSTRACT
Amino-anthranilic acid derivatives have been identified as a new class of low serum shifted, high affinity full agonists of the human orphan G-protein-coupled receptor GPR109a with improved ADME properties.
Subject(s)
Drug Discovery , Receptors, G-Protein-Coupled/agonists , Animals , Fluorine/chemistry , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Niacin/chemical synthesis , Niacin/chemistry , Niacin/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Receptors, NicotinicABSTRACT
5-Alkyl and aryl-pyrazole-acids have been identified as a new class of selective, small-molecule, agonists of the human orphan G-protein-coupled receptor GPR109a, a high affinity receptor for the HDL-raising drug nicotinic acid.
Subject(s)
Pyrazoles/chemistry , Receptors, G-Protein-Coupled/agonists , Animals , Fatty Acids/metabolism , Humans , Mice , Niacin/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Receptors, G-Protein-Coupled/metabolism , Receptors, Nicotinic/metabolismABSTRACT
5-Alkyl and aryl-pyrazole-tetrazoles have been identified as a new class of selective, small-molecule, agonists of the human G-protein-coupled receptor GPR109a, a high affinity receptor for the HDL-raising drug nicotinic acid.
Subject(s)
Pyrazoles/chemistry , Receptors, G-Protein-Coupled/agonists , Tetrazoles/chemistry , Animals , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Pyrazoles/pharmacology , Receptors, G-Protein-Coupled/deficiency , Receptors, G-Protein-Coupled/physiology , Receptors, Nicotinic/deficiency , Receptors, Nicotinic/physiology , Tetrazoles/pharmacology , Vasodilation/drug effects , Vasodilation/physiologyABSTRACT
The chirality of biological receptors often requires syntheses of therapeutic compounds in single enantiomer form. The field of asymmetric catalysis addresses enantioselective synthesis with chiral catalysts. Chemical differentiation of sites within molecules that are separated in space by long distances presents special challenges to chiral catalysts. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity for the catalyst. The extreme of catalyst complexity could be defined by macromolecular enzymes and their amazing capacity to effect stereospecific reactions over long distances between reactive sites and enzyme-substrate contacts. We report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a very long distance.
