Giorgio Pentassuglia

Discovery process and pharmacological characterization of 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) as a potent, selective, and orally active NK1 receptor antagonist.

In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.

1,5-Benzodiazepines as CCK-B antagonists. Effect of halogen substitution at the benzo-fused ring on potency and selectivity

Abstract Some 1,5-benzodiazepines substituted with halogen atoms in the benzo-fused ring were synthesized and evaluated as CCK antagonists at both CCK-A and CCK-B receptors. Details of the binding of these agents to both receptors are reported and discussed briefly.

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.

Efficient synthesis of novel benzo-[e]-[1,4]-diazepine derivatives

Abstract Following two efficient synthetic routes a novel series of benzo-[e]-[1,4]-diazepine derivatives, bearing an unusual Z exo-methylencarbamoyl side chain at the C-5 position, have been prepared to identify new antagonists of the glycine binding site associated with NMDA receptor.

Synthesis and pharmacological characterisation of a conformationally restrained series of indole-2-carboxylates as in vivo potent glycine antagonists

After the identification of GV150526, the indole-2-carboxylate template was further explored in order to identify novel potential anti-stroke agents. In particular, the SAR of the side chain present at the C-3 position of the indole nucleus was widely studied. In this paper, the synthesis and the pharmacological profile of a further class of conformationally restricted analogues of GV150526 as in vitro and in vivo potent glycine antagonists is reported. In particular, a pyrazolidinone derivative was identified as a potent neuroprotective agent in animal models of cerebral ischaemia.

Substituted Indole‐2‐carboxylates as Potent Antagonists of the Glycine Binding Site Associated with the NMDA Receptor

A novel series of indole‐2‐carboxylate analogues of GV150526 (1) in which the propenoic double bond was substituted with different “probes” or replaced by a isosteric cyclopropyl moiety were synthesized and evaluated for their affinity profile in order to obtain further information on the pharmacophoric model of the glycine binding site associated to the NMDA receptor.

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 4-AMINO TRINEMS

Abstract This article deals with the study carried out on the synthesis of 4-amino substituted trinems 1 starting from the key-intermediate (3S, 4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1′R, 2′S, 3′R)-1′,2′-epoxycyclohex-3′-yl]azetidin-2-one 2 . In particular, epoxide opening with various amines and subsequent cyclization to the corresponding trinems were explored. Their synthesis and antimicrobial activity are reported.

Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK1 receptor antagonists

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.

Synthesis and Evaluation of 1,5‐Benzodiazepines with Bridged Cycloalkyl Substituents at the N‐1 Position as Potent and Selective CCK‐B Ligands

The synthesis and biological evaluation of 3‐ureido and 3‐carbamate derivatives of 1,5‐benzodiazepines bearing bridged cycloalkyl substituents at N‐1 are reported. Their activity as CCK‐B receptor ligands is briefly discussed.

Novel Synthesis of Ethyl 3-(Bromoacetyl)-4,6-dichloro-1H-indole-2-carboxylate as Useful Intermediate in the Preparation of Potential Glycine Site Antagonists

Abstract A novel synthesis of ethyl 3-(bromoacetyl)-4,6-dichloro-1H-indole-2-carboxylate is described. The efficient preparation of this key intermediate allowed to obtain the thiazole derivative 2 as potential glycine site N-metyhl-D-aspartate receptor antagonist.