Tino Rossi

Analogues of 4,5-bis(3,5-dichlorophenyl)-2-trifluoromethyl-1H-imidazole as potential antibacterial agents

A preliminary exploration of analogues of 4,5-bis(3,5-dichlorophenyl)-2-trifluoromethyl-1H-imidazole, 1, as novel antibacterial agents was carried out to determine the basic features of the structure responsible for the observed biological activity. The presence of two aryl rings, the imidazole NH and either a good electron withdrawing group or an aldehyde or amino group at C-2 were required for good levels of activity against methicillin resistant Staphylococcus aureus (MRSA).

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.

Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates

As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the ‘optimal’ absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.

The synthesis of a key intermediate of tricyclic beta-lactam antibiotics

Abstract By employing an intramolecular Sakurai-type olefination it was possible to obtain the olefin 5 , a key intermediate in the synthesis of the broad spectrum tricyclic β-lactam antibiotic GG-326 1 .

Nitrate ester derivatives from epoxides using CAN: Efficient preparation of key intermediates in the synthesis of 4-alkoxytrinems

Abstract A regio and stereoselective opening reaction of epoxide with CAN (0.5 equivalents) in aprotic solvents is descried. This novel reaction allowed the preparation of versatile nitrate ester derivatives as useful intermediates in the synthesis of trinems widely substituted at the position C-4.

The stereoselective synthesis of a key intermediate of the trinem antibiotic sanfetrinem

Abstract By modulating the reactivity of the Lewis acid promoter it was possible to obtain, in a single stereoselective condensation step, the methoxyketone 7, an advanced intermediate in the synthesis of Sanfetrinem GV104326.

Dopamine D3 receptor antagonists: The quest for a potentially selective PET ligand. Part 3: Radiosynthesis and in vivo studies

Compound 1 is a potent and selective antagonist of the dopamine D(3) receptor. With the aim of developing a carbon-11 labeled ligand for the dopamine D(3) receptor, 1 was selected as a potential PET probe. [(11)C]1 was obtained by palladium catalyzed cross coupling using [(11)C]cyanide and 4 with a specific activity of 55.5+/-25.9GBq/micromol (1.5+/-0.7Ci/micromol). [(11)C]1 was tested in porcine and non-human primate models to assess its potential as a radioligand for PET imaging of the dopamine D(3) receptor. We conclude that in both species and despite appropriate in vitro properties, [(11)C]1 does not show any specific signal for the dopamine D(3) receptor.

The stereoselective synthesis of 4-formyltrinem, a key intermediate for novel trinems

Abstract The stereoselective synthesis of a protected 4-formyltrinem 8 was accomplished in good yield. This compound is a potential intermediate in the synthesis of a wide range of 4-alkyl and alkenyl substituted trinem antibiotics, as evidenced by its reaction with a series of phosphoranes and phosphonates.

Highly Diastereoselective Synthesis of 4-N-Methylformamidino Trinem (GV129606), a Potent Antibacterial Agent

Abstract In this paper a highly diastereoselective synthesis of 4-N-methylformamidino trinem 3 is reported. The route offers advantages compared to that previously used, i.e. the higher overall yield, the robustness, the avoidance of toxic reagents. Most of the compounds were isolated by precipitation, therefore reducing the number of chromatographic separations. The efficient conversion of 4-N-methylamino trinem 11 into GV129606 3, was obtained by a new methodology in which a scavenger resin was used. The route presented in this paper allowed the preparation of the material required for early development studies and demonstrates the versatility of cyclohexenyl azetidinone 12 in the synthesis of 4-substituted trinems.

Synthesis and antibacterial activity of 4- and 8-methoxy trinems

Abstract The synthesis of all the isomers of 8-methoxy-(9 S ,10 S ,12 R )-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo-[7.2.0.0 3,8 ]-undec-2-ene-carboxylates 2 and 4-methoxy-(9 R ,10 S ,12 R )-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo-[7.2.0.0 3,8 ]-undec-2-ene-carboxylates 3 is described. The biological data obtained indicated that the (4 S ,8 S )-4-methoxy derivative ( 3b ) is the best compound in terms of microbiological activity, breadth of spectrum of action and stability to hydrolytic enzymes, namely β-lactamases.