ABSTRACT
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 , StereoisomerismABSTRACT
The synthesis of a series of carbazole derivatives and their SAR at the NPY Y1 receptor is described. Modulation of physicochemical properties by appropriate decoration led to the identification of a high-affinity NPY Y1 antagonist that shows high brain penetration and modest oral bioavailability.
Subject(s)
Carbazoles/chemical synthesis , Carbazoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Biological Availability , Brain/drug effects , Brain/metabolism , CHO Cells , Carbazoles/pharmacokinetics , Chemical Phenomena , Chemistry, Physical , Cricetinae , Cricetulus , Half-Life , Indicators and Reagents , Male , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The SAR of a new series of tetrahydrocarbazole derivatives is described: the appropriate decoration of this template led to the identification of a new class of NPY-1 antagonists showing good in vitro potency and a promising in vivo pharmacokinetic profile in rat.
