Subject(s)
Appetite Stimulants/chemistry , Body Weight/drug effects , Eating/drug effects , Ghrelin/antagonists & inhibitors , Hydrazines/chemistry , Hydrazines/pharmacology , Receptors, Ghrelin , Animals , Appetite Stimulants/pharmacokinetics , Appetite Stimulants/pharmacology , Circular Dichroism , Female , Ghrelin/metabolism , Hydrazines/pharmacokinetics , Ligands , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/antagonists & inhibitors , Structure-Activity RelationshipSubject(s)
Hydrazines/chemistry , Receptors, Ghrelin/antagonists & inhibitors , Cell Line , Drug Evaluation, Preclinical , Feeding and Eating Disorders/drug therapy , Humans , Hydrazines/chemical synthesis , Hydrazines/therapeutic use , Receptors, Ghrelin/metabolism , Structure-Activity RelationshipSubject(s)
Anxiety/drug therapy , Depression/drug therapy , Drug Design , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anxiety/pathology , Corticotropin-Releasing Hormone/metabolism , Depression/pathology , Models, Chemical , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.
Subject(s)
Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Dose-Response Relationship, Drug , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Protein Binding , Pyrimidines/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Vocalization, Animal/drug effectsABSTRACT
Within the continuous quest for the discovery of novel compounds able to treat anxiety and depression, the generation of a pharmacophore model for 5-HT2C receptor antagonists and the discovery of a new class of potent and selective 5-HT2C molecules are reported.