Serge Halazy

G-protein coupled receptors bivalent ligands and drug design

G-protein coupled receptors (GPCR) represent a large family of receptors, which have been and still are targets of choice for drug discovery. Among the different tools offered to medicinal chemists to design potent and selective GPCR agonists or antagonists, the bivalent-ligand approach (which consists of bridging two pharmacophores in a single ligand) has proven to be, in many cases, valuable to improve potency, selectivity, intrinsic activity and in vivo profile of the corresponding monomer. This review will focus on GPCR ligands in drug research with particular emphasis on the most recent progress in the field.

Design and synthesis of new potent, silent 5-HT1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors

Hybrid molecules built up by covalent coupling of aminopropanol derivatives (especially pindolol) with antidepressant drugs like fluoxetine, paroxetine or milnacipran were found to be potent and silent 5-HT1A antagonists (KB < 1 nM for 7c and 9a).

5-HT1B/1D antagonists and depression

The molecular pharmacology, functional role and behavioural implications of central 5-HT1B/1D receptors suggest that these particular receptor subtypes probably play an important role in brain serotonin neurotransmission. This article summarises the rationale for considering 5-HT1B/1D antagonists as potential new, fast-acting antidepressants and describes the development of recent selective potent 5-HT1B/1D antagonists, reviewing both the primary and patent literature.

Original syntheses of epoxides involving organoselenium intermediates

Syntheses a partir de composes carbonyles et de sels de selenonium, dalkyl phenyl selenones ou de β-hydroxy seleniures

Phosphonate derivatives of N9-benzylguanine: a new class of potent purine nucleoside phosphorylase inhibitors

New phosphonate derivatives of N 9 -benzylguanine ( 5a – 5d ) have been designed and prepared as purine nucleoside phosphorylase inhibitors. Enzyme inhibition studies with PNP from calf spleen or human erythrocytes demonstrate that the trifluorophosphonate 5b , the fluorovinylphosphonate 5c and the vinylphosphonate 5d , with K i values around 1 nM, are the most potent inhibitors of PNP ever reported.

Arylpiperazide derivatives of phenylpiperazines as a new class of potent and selective 5-HT1B receptor antagonists

Abstract A new series of arylpiperazide derivatives of phenylpiperazines of general formula 4 has been prepared and evaluated as 5-HT1B receptor antagonists. In vitro experiments at human cloned 5-HT1B receptors show that these derivatives are potent and selective 5-HT1B receptor antagonists. Among them, compound 4f was found to be orally active, to gain access to the CNS and more importantly to induce an increase in extracellular brain 5-HT upon systemic administration.

Enzymatic phosphorylation and pyrophosphorylation of 2',3'-dideoxyadenosine-5'-monophosphate, a key metabolite in the pathway for activation of the anti-HIV (human immunodeficiency virus) agent 2',3'-dideoxyinosine.

2,3-Dideoxyadenosine-5-monophosphate (ddAMP) is a key intermediate in the metabolic pathway involved in the activation of the anti-retroviral agent 2,3-dideoxyinosine (ddI) to 2,3-dideoxyadenosine-5-triphosphate (ddATP). The potential phosphorylation of ddAMP by adenylate kinase (myokinase) and pyrophosphorylation by the reverse reaction of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase were investigated. Using ATP as phosphate donor, ddAMP was phosphorylated by adenylate kinase with an efficiency of 8.8% of that for AMP, as estimated from the Vmax/Km ratios. In the presence of PRPP, Escherichia coli and rat PRPP synthetases catalysed the pyrophosphorylation of ddAMP with efficiencies of 52 and 35% of that determined for AMP, respectively. Two carbocyclic phosphonate analogues of ddAMP were not substrates of adenylate kinase. Yet, they were pyrophosphorylated by both PRPP synthetases, albeit less efficiently than ddAMP. In vivo, the usual function of PRPP synthetase is to synthesize PRPP from ribose-5-phosphate and ATP. In the forward reaction ddATP proved to be a substrate as efficient as ATP for rat PRPP synthetase. ddATP was also studied as a potential phosphate donor in the reaction catalysed by adenylate kinase with AMP as phosphate acceptor and found to be as efficient as ATP. The relevance of these in vitro results to the in vivo situation is discussed.

Synthesis and Antiviral Properties of New Cycloalkanol Derivatives of Guanine

Abstract New conformationaly constrained cycloalkanol derivatives of guanine have been prepared as potential anti-herpetic agents. None of these compounds was found to inhibit HSV or CMV replication in cell culture but some of them show some antagonism or synergism towards acyclovir protecting effect.

Synthesis, antiviral activity and enzymatic phosphorylation of 9-phosphonopentenyl derivatives of guanine

(E)-9-(5-Phosphonopent-4-enyl)guanine and (E)-9-[3-(hydroxymethyl)-5- phosphonopent-4-enyl]guanine which bear a vinyl phosphonate moiety as a mimic of the phosphate group were synthesized. Their activities against human immunodeficiency virus type-1 (HIV-1), herpes simplex virus type-1 (HSV-1) and human cytomegalovirus (HCMV) were evaluated in vitro in parallel with those of 9-(5-phosphonopentyl)guanine and 9-(5,5-difluoro-5- phosphonopentyl)guanine. Both vinyl phosphonates exhibited anti-HIV-1 and anti-HCMV activities, whereas the methyl- and difluoromethyl phosphonate analogues were inactive. The selectivity index, calculated as the ratio of the toxicity for the host cells (50% reduction in cell viability or in [methyl-3H]thymidine incorporation) to the 50% inhibitory concentration for HIV-1 replication, was the highest for (E)-9-[3-(hydroxymethyl)-5-phosphonopent-4-enyl]guanine. The acyclonucleotide analogues were also studied as substrates of guanylate kinase, an enzyme believed to play a critical role in the conversion of acyclic phosphate and phosphonate derivatives of guanine to their antivirally active diphosphate derivatives. (E)-9-(5-Phosphonopent-4- enyl)guanine and (E)-9-[3-(hydroxymethyl)-5-phosphonopent-4-enyl]guanine were good substrates of guanylate kinase, being phosphorylated with efficiencies of 14 and 36% of that determined for GMP, respectively. These results contrast with the poor efficiency found for 9-(5-phosphonopentyl)guanine (0.3%) and the lack of phosphorylation of 9-(5,5-difluoro-5-phosphonopentyl)guanine by guanylate kinase (Navé et al. (1992) Arch. Biochem. Biophys. 295, 253-257). The role of the vinyl phosphonate group in the expression of the anti-HIV-1 activity of the phosphonopentenyl derivatives of guanine is discussed.

Studies Towards the Synthesis of the Saturated and Unsaturated Carbocyclic Methylene Phosphonate Analogs of Dideoxyadenosine

Abstract The synthesis of the saturated carbocyclic methylene phosphonate analog of ddAMP is described by two different methods (epoxyde opening and “purinoselenylation”). Studies towards the formation of 2′,3′ unsaturated analogs by selenoxyde or mesylate elimination are also reported.