ABSTRACT
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.
Subject(s)
Azabicyclo Compounds/chemistry , Oxadiazoles/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Protein Binding , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Corticotropin-Releasing Hormone/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolismSubject(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 RelationshipABSTRACT
A focused exploration targeting conformationally restricted analogues of Vestipitant, resulted in the discovery of novel, in vitro potent NK(1) antagonists. In particular, two of the compounds reported exhibited a good pharmacokinetic (PK) profile and produced anxiolytic-like effects in the gerbil foot tapping (GFT) in vivo model.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Neurokinin-1 Receptor Antagonists , Piperidines/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Drug Design , Fluorobenzenes , Humans , Molecular Conformation , Piperidines/chemistry , Piperidines/pharmacokinetics , Receptors, Neurokinin-1/metabolismABSTRACT
To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Female , Forelimb/drug effects , Gerbillinae , Humans , Male , Models, Chemical , Molecular Structure , Motor Activity/drug effects , Psychological Tests , Pyridines/chemistry , Pyrroles/chemistry , Rats , Rats, Sprague-Dawley , Stereoisomerism , Ultrasonics , Vocalization, Animal/drug effectsABSTRACT
In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.
Subject(s)
Computer Simulation , Pyridines/pharmacology , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Binding Sites , CHO Cells , Cricetinae , Cricetulus , Drug Design , Ligands , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Quantitative Structure-Activity Relationship , StereoisomerismSubject(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
Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.
Subject(s)
Naphthalenes/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Administration, Oral , Humans , Naphthalenes/administration & dosage , Naphthalenes/chemistry , Naphthalenes/pharmacokinetics , Recombinant Proteins/antagonists & inhibitorsABSTRACT
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
The potency and selectivity of a previous series of low molecular weight thrombin inhibitors were improved through modifications of the P1 and P3 residues. Introduction of diphenyl substituted sulfonamides in the P3 moiety led to highly efficacious compounds. By correctly selecting the combination of P1 and P3 residues, high levels of potency, selectivity and in vivo efficacy were obtained.