1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane: further insights into a class of triple re-uptake inhibitors.

Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.

6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: a new potent and selective triple reuptake inhibitor.

A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.

1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: a new series of potent and selective triple reuptake inhibitors.

The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.

Synthesis and pharmacological characterization of novel druglike corticotropin-releasing factor 1 antagonists.

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.

Dihydropyrrole[2,3-d]pyridine derivatives as novel corticotropin-releasing factor-1 antagonists: mapping of the receptor binding pocket by in silico docking studies.

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.

Cyclopenta[d]pyrimidines and dihydropyrrolo[2,3-d]pyrimidines as potent and selective corticotropin-releasing factor 1 receptor antagonists.

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.