ABSTRACT
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Subject(s)
Pteridines/chemistry , Pyrazines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Half-Life , Pteridines/chemical synthesis , Pteridines/pharmacokinetics , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Structure-Activity RelationshipABSTRACT
A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. Selected compounds proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, we describe an in vitro intrinsic clearance-based approach to the optimization of pyrazinone-based CRF(1) receptor antagonists wherein sites of metabolism were identified by incubation with human liver microsomes. It was found that the rate of metabolism could be decreased by incorporation of appropriate substituents at the primary sites of metabolism. This led to the discovery of compound 12x, a highly potent (IC(50) = 1.0 nM) and selective CRF(1) receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.
Subject(s)
Pyrazines/pharmacology , Pyrazines/pharmacokinetics , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Humans , Inhibitory Concentration 50 , Male , Metabolic Clearance Rate , Pyrazines/chemistry , Pyrazines/metabolism , Rats , Receptors, Corticotropin-Releasing Hormone/metabolismABSTRACT
Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.
Subject(s)
Pyrazines/chemistry , Pyrazines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Cell Line, Tumor , Humans , Macaca fascicularis , Male , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A novel series of 2-anilino-3-phenylsulfonyl-6-methylpyridines was synthesized and evaluated as corticotropin-releasing factor receptor ligands. Structure-activity relationship studies focused primarily on optimization of the 3-phenylsulfonyl group. Compounds within this series were identified which showed potent binding affinity for the CRF1 receptor. Selected compounds were examined in a rat pharmacokinetic study and were found to have oral bioavailabilities ranging from 16 to 35%.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Administration, Oral , Animals , Crystallography, X-Ray , Ligands , Models, Molecular , Molecular Structure , Pyridines/administration & dosage , Rats , Structure-Activity Relationship , Tissue DistributionABSTRACT
A series of high affinity CRF receptor ligands with an imidazo[4,5-b]pyridine core is described. Individual analogues were synthesized and tested in a rat CRF receptor binding assay. The best compounds were further tested in the dog N-in-1 pharmacokinetic model to assess plasma levels at 1mg/kg (po) and in the rat situational anxiety model to assess anxiolytic efficacy at 3mg/kg (po). The structure-activity relationships for good receptor binding affinity are described herein.
Subject(s)
Anti-Anxiety Agents/pharmacology , Pyridines/pharmacology , Receptors, Corticotropin-Releasing Hormone/metabolism , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/metabolism , Anxiety Disorders/drug therapy , Dogs , Half-Life , Ligands , Metabolic Clearance Rate , Pyridines/chemical synthesis , Pyridines/metabolism , Rats , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A series of high affinity CRF receptor ligands with an imidazo[4,5-c]pyridine core is described. Individual analogues were synthesized and tested in vitro in rat brain receptors to determine binding affinity. The best compound was further tested in the dog N-in-1 pharmacokinetic model to assess oral bioavailability at 1 mg/kg po.
Subject(s)
Anti-Anxiety Agents/pharmacology , Pyridines/pharmacology , Receptors, Corticotropin-Releasing Hormone/metabolism , Administration, Oral , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/metabolism , Anxiety Disorders/drug therapy , Biological Availability , Dogs , Ligands , Pyridines/chemical synthesis , Pyridines/metabolism , Rats , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A series of imidazo[4,5-b]pyridines with a 7-(3-pyridyl) substituent is described as high affinity CRF receptor ligands. Individual analogues were synthesized from key intermediates obtained via palladium-catalyzed coupling of 3-pyridyl zinc or boronic acid organometallic intermediates with 2-benzyloxy-4-chloro-3-nitropyridine 12.
