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
The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.
Subject(s)
Cyclohexenes/chemical synthesis , Cyclohexenes/pharmacology , Cyclopentanes/chemical synthesis , Cyclopentanes/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacology , ortho-Aminobenzoates/chemical synthesis , ortho-Aminobenzoates/pharmacology , Animals , Aryl Hydrocarbon Hydroxylases/drug effects , Cyclohexenes/chemistry , Cyclohexenes/pharmacokinetics , Cyclopentanes/chemistry , Cyclopentanes/pharmacokinetics , Cytochrome P-450 CYP2C8 , Cytochrome P-450 CYP2C9 , Drug Design , Humans , Mice , Nicotinic Agonists/chemistry , Nicotinic Antagonists/pharmacology , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacokineticsABSTRACT
High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1 receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Receptors, Cholecystokinin/agonists , Amides/chemistry , Animals , Anti-Obesity Agents/chemistry , Chemokines, CC , Combinatorial Chemistry Techniques , Eating/drug effects , Gallbladder Emptying/drug effects , Humans , Imidazoles/chemistry , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.
Subject(s)
Receptors, G-Protein-Coupled/agonists , ortho-Aminobenzoates/chemical synthesis , Amides/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Cytochrome P-450 CYP2C8 , Cytochrome P-450 CYP2C9 , Humans , In Vitro Techniques , Mice , Microsomes, Liver/metabolism , Radioligand Assay , Receptors, Nicotinic , Structure-Activity Relationship , ortho-Aminobenzoates/pharmacokinetics , ortho-Aminobenzoates/pharmacologyABSTRACT
Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.
Subject(s)
Carboxylic Acids/pharmacology , Cyclohexanecarboxylic Acids/pharmacology , Cyclohexenes/chemistry , Drug Discovery , Oxadiazoles/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Area Under Curve , Binding, Competitive , CHO Cells , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacokinetics , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacokinetics , Dogs , Drug Evaluation, Preclinical , Fatty Acids, Nonesterified/blood , Humans , Metabolic Clearance Rate , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Chemical , Molecular Structure , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , Rats , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , Vasodilation/drug effectsABSTRACT
Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.