Aldo Feriani

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.

Synthesis and pharmacological characterisation of 2,4-Dicarboxy-pyrroles as selective non-Competitive mGluR1 antagonists

Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.

Benzoazepine derivative as potent antagonists of the glycine binding site associated to the NMDA receptor

A series of benzoazepine derivatives, bearing suitable substituents at the C-3 position, was designed and evaluated by superimposition with the pharmacophore model of the glycine binding site. To fully explore the SAR of this class of compounds and to allow the preparation of new different compounds at the C-3 position, appropriate synthetic routes were set up. The benzoazepines were evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. This further analysis confirmed the preliminary results previously reported and that compound 27 is the most promising compound (Ki=32 nM, ED(50)=0.09 mg/kg, i.v.) in this series. Significant neuroprotective effect was observed after both pre- and post-ischaemia administration in the MCAo model. In particular, after post-ischaemia administration, it was found to be still effective when the administration was delayed up to 6 h after occlusion of the middle cerebral artery.

Novel morpholine scaffolds as selective dopamine (DA) D3 receptor antagonists

A new series of morpholine derivatives has been identified as selective DA D3 receptor antagonists; their in vitro profile and pharmacokinetic data are provided.

1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists.

A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.

Cholinergic agents structurally related to furtrethonium. 1

Abstract A series of 5-substituted-2-(dimethylaminomethyl)-furyl derivatives 4 was prepared, with the aim of discovering novel antimuscarinic agents which are selective for smooth muscle as opposed to cardiac tissue. Both non-quaternary and quaternary ammonium compounds were synthesised. The agonist starting point, furtrethonium 3 , was gradually transformed into antagonist by introduction of lipophilic and bulky groups in position 5 of this molecule. In particular, the introduction of α-hydroxy-α-cyclohexylbenzyl moiety (compound 9b ), a lipophilic group characteristic of antimuscarinic agents, caused an appreciable increase of the antagonists potency, and the lengthening of the distance between this lipophilic group and the furan ring, obtained by introduction of an ester, ether or amide group, led to some selectivity towards smooth muscle (compounds 19, 21, 25 ). Interestingly, compound 19 , with an ester moiety as a spacer group, proved to be at least 20 times more potent in rat ileum (p K B = 7.3) and rat bladder (p K B = 7.2) than guinea-pig atria (p K B = 5.9).

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.

Synthesis and biological evaluation of 4-heterotribactams

Abstract The synthesis and the preliminary microbiological activity of some tryciclic β-lactam derivatives designed combining the structural features of the natural carbapenems and the synthetic “tribactams” are described.

Synthesis and structure-activity relationship of new 1,5-dialkyl-1,5-benzodiazepines as cholecystokinin-2 receptor antagonists.

This article deals with the synthesis and the activities of some 1,5-dialkyl-3-arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 was replaced with more hydrophilic substituents, like alkyl groups bearing basic functions. In some cases, the resolution of the racemic key intermediates 3-amino-benzodiazepines was also accomplished. Among the compounds synthesized and characterised so far in this class, the 5-morpholinoethyl derivative 54, was selected as potential follow up of GV150013 and submitted for further evaluation.

1,2,4-Triazolyl 5-Azaspiro[2.4]heptanes: Lead Identification and Early Lead Optimization of a New Series of Potent and Selective Dopamine D3 Receptor Antagonists

A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies.