ABSTRACT
G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.
Subject(s)
Fatty Acids, Nonesterified/blood , Pyrazoles/therapeutic use , Receptors, G-Protein-Coupled/agonists , Animals , Humans , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/therapeutic use , Male , Niacin/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Rats , Receptors, G-Protein-Coupled/drug effects , Receptors, Nicotinic/drug effects , Stereoisomerism , Vasodilator Agents/pharmacologyABSTRACT
A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin 5-HT2 Receptor Antagonists/chemistry , Serotonin 5-HT2 Receptor Antagonists/therapeutic use , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep/drug effects , Animals , Humans , Rats , Serotonin 5-HT2 Receptor Antagonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.
Subject(s)
Amides/chemical synthesis , Piperazines/chemical synthesis , Pyrazoles/chemical synthesis , Serotonin 5-HT2 Receptor Antagonists , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep/drug effects , Administration, Oral , Amides/pharmacokinetics , Amides/pharmacology , Animals , Biological Availability , Blood Proteins/metabolism , Brain/metabolism , Dogs , Drug Inverse Agonism , Haplorhini , Humans , Male , Microsomes, Liver/metabolism , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at lowering free fatty acids in vitro and in vivo.
Subject(s)
Pyrazoles/chemistry , Receptors, G-Protein-Coupled/agonists , Tetrazoles/chemistry , Vasodilator Agents/chemistry , Animals , Dogs , Haplorhini , Humans , Mice , Rats , Receptors, G-Protein-Coupled/metabolism , Receptors, Nicotinic/metabolism , Tetrazoles/chemical synthesis , Tetrazoles/pharmacokinetics , Vasodilator Agents/chemical synthesis , Vasodilator Agents/pharmacokineticsABSTRACT
The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.
Subject(s)
Hypolipidemic Agents/pharmacology , Pyrazoles/pharmacokinetics , Receptors, G-Protein-Coupled/agonists , Tetrazoles/pharmacokinetics , Adipocytes/drug effects , Animals , Fatty Acids, Nonesterified/blood , Humans , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/therapeutic use , Lipolysis/drug effects , Male , Mice , Mice, Inbred C57BL , Pyrazoles/chemical synthesis , Receptors, Nicotinic , Tetrazoles/chemical synthesis , Vasodilation/drug effectsABSTRACT
A series of 3-nitro-4-substituted-aminobenzoic acids were prepared and found to act as potent and highly selective agonists of the orphan human GPCR GPR109b, a low affinity receptor for niacin. No activity was observed at the closely homologous high affinity niacin receptor, GPR109a. A second series, comprising 6-amino-substituted nicotinic acids was, also prepared and several analogues showed comparable activity to the nitroaryl series.
Subject(s)
Benzoates/chemistry , Nicotinic Acids/chemistry , Receptors, G-Protein-Coupled/agonists , Animals , Benzoates/agonists , Benzoates/metabolism , CHO Cells , Cricetinae , Cricetulus , Humans , Niacin/metabolism , Nicotinic Acids/agonists , Nicotinic Acids/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/physiology , Receptors, Nicotinic/metabolism , Receptors, Nicotinic/physiology , Structure-Activity RelationshipABSTRACT
A series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.
Subject(s)
Acids/chemistry , Fluorine/chemistry , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Fatty Acids/metabolism , Ligands , Male , Mice , Molecular Structure , Nicotinic Agonists/chemical synthesis , Pyrazoles/chemical synthesis , Rats , Receptors, G-Protein-Coupled/metabolism , Receptors, Nicotinic/metabolism , Structure-Activity RelationshipABSTRACT
A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.
Subject(s)
Acids, Heterocyclic/chemistry , Chemistry, Pharmaceutical/methods , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/chemistry , Receptors, Nicotinic/chemistry , Adipocytes/metabolism , Animals , Cyclic AMP/metabolism , Drug Design , Humans , Kinetics , Models, Chemical , Niacin/chemistry , Pyrazoles/chemistry , Rats , Spleen/metabolismABSTRACT
1-Substituted benzotriazole carboxylic acids have been identified as the first reported examples of selective small-molecule agonists of the human orphan G-protein-coupled receptor GPR109b (HM74), a low-affinity receptor for the HDL-raising drug niacin. No activity was observed at the highly homologous high-affinity niacin receptor GPR109a (HM74A). The high degree of selectivity was attributed to a difference in the amino acid sequence adjacent to a key arginine-ligand interaction allowing somewhat larger ligands to be tolerated by GPR109b.