ABSTRACT
The discovery of a novel, selective and fully efficacious CB2 agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound 6 was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB2 receptor to avoid tachyphylaxis. Based on its overall favorable preclinical profile, 6 (APD371) was selected for further development for the treatment of pain.
ABSTRACT
The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.
Subject(s)
Analgesics, Non-Narcotic/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Inflammation/drug therapy , Microsomes, Liver/drug effects , Osteoarthritis/drug therapy , Pain/drug therapy , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB2/agonists , Administration, Oral , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/chemistry , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Inflammation/metabolism , Male , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Osteoarthritis/metabolism , Pain/metabolism , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/agonists , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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
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
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
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 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 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
Recently identified GPCRs, GPR109a and GPR109b, the high and low affinity receptors for niacin, may represent good targets for the development of HDL elevating drugs for the treatment of atherosclerosis. Acifran, an agonist of both receptors, has been tested in human subjects, yet until recently very few analogs had been reported. We describe a series of acifran analogs prepared using newly developed synthetic pathways and evaluated as agonists for GPR109a and GPR109b, resulting in identification of compounds with improved activity at these receptors.
