ABSTRACT
A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.
Subject(s)
Amides/chemistry , Amides/pharmacology , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Receptor, Metabotropic Glutamate 5/metabolism , Allosteric Regulation/drug effects , Amides/pharmacokinetics , Animals , Behavior, Animal/drug effects , Cyclopropanes/pharmacokinetics , Glutamic Acid/chemistry , Glutamic Acid/metabolism , Indazoles/chemistry , Indazoles/pharmacokinetics , Indazoles/pharmacology , Male , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5/chemistry , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.
Subject(s)
Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/pharmacology , Cognition Disorders/drug therapy , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacology , Nootropic Agents/chemical synthesis , Nootropic Agents/pharmacology , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Receptors, Nicotinic/chemistry , Schizophrenia/drug therapy , Animals , Azabicyclo Compounds/chemistry , Biological Availability , Cells, Cultured , Epithelial Cells/drug effects , Female , Hippocampus/drug effects , Humans , Kidney/cytology , Kidney/drug effects , Microsomes, Liver/drug effects , Nicotinic Agonists/chemistry , Nootropic Agents/chemistry , Oocytes/drug effects , Oxazoles/chemistry , Rats , Skin/cytology , Skin/drug effects , Structure-Activity Relationship , Xenopus laevis/growth & development , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-diazabicyclo[3.2.2]nonane phenyl carbamate series of alpha7 nAChR agonists is described. The development of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selective, high affinity alpha7 agonists as excellent leads for further evaluation is discussed, along with key physicochemical and pharmacokinetic data highlighting their lead potential.
