André Giroux

MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation

Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal prostaglandin E2 (PGE2) synthase in the cyclooxygenase pathway. Inhibitors of mPGES-1 may block PGE2 production and relieve inflammatory symptoms. To test the hypothesis, we evaluated the antipyretic and analgesic properties of a novel and selective mPGES-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro-[9,10-d]imidazol-2-yl)isophthalonitrile], in animal models of inflammation. MF63 potently inhibited the human mPGES-1 enzyme (IC50 = 1.3 nM), with a high degree (>1000-fold) of selectivity over other prostanoid synthases. In rodent species, MF63 strongly inhibited guinea pig mPGES-1 (IC50 = 0.9 nM) but not the mouse or rat enzyme. When tested in the guinea pig and a knock-in (KI) mouse expressing human mPGES-1, the compound selectively suppressed the synthesis of PGE2, but not other prostaglandins inhibitable by nonsteroidal anti-inflammatory drugs (NSAIDs), yet retained NSAID-like efficacy at inhibiting lipopolysaccharide-induced pyresis, hyperalgesia, and iodoacetate-induced osteoarthritic pain. In addition, MF63 did not cause NSAID-like gastrointestinal toxic effects, such as mucosal erosions or leakage in the KI mice or nonhuman primates, although it markedly inhibited PGE2 synthesis in the KI mouse stomach. Our data demonstrate that mPGES-1 inhibition leads to effective relief of both pyresis and inflammatory pain in preclinical models of inflammation and may be a useful approach for treating inflammatory diseases.

One pot biaryl synthesis via in situ boronate formation

Abstract The palladium-catalyzed cross-coupling reaction of aryl halides or aryl triflates with diborane 1 yielded structurally diverse aryl boronates which were reacted in situ with aryl halides or aryl to triflates afford a variety of biaryls in moderate to high yield.

Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors

Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 microM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development.

Neuroprotective effects of M826, a reversible caspase-3 inhibitor, in the rat malonate model of Huntington's disease

Caspases, key enzymes in the apoptosis pathway, have been detected in the brain of HD patients and in animal models of the disease. In the present study, we investigated the neuroprotective properties of a new, reversible, caspase‐3‐specific inhibitor, M826 (3‐({(2S)‐2‐[5‐tert‐butyl‐3‐{[(4‐methyl‐1,2,5‐oxadiazol‐3‐yl)methyl]amino}‐2‐oxopyrazin‐1(2H)‐yl]butanoyl}amino)‐5‐[hexyl(methyl)amino]‐4‐oxopentanoic acid), in a rat malonate model of HD. Pharmacokinetic and autoradiography studies after intrastriatal (i.str.) injection of 1.5 nmol of M826 or its tritiated analogue [3H]M826 indicated that the compound diffused within the entire striatum. The elimination half‐life (T1/2) of M826 in the rat striatum was 3 h. I.str. injection of 1.5 nmol of M826 10 min after malonate infusion induced a significant reduction (66%) in the number of neurones expressing active caspase‐3 in the ipsilateral striatum. Inhibition of active caspase‐3 translated into a significant but moderate reduction (39%) of the lesion volume, and of cell death (24%), 24 h after injury. The efficacy of M826 at inhibiting cell death was comparable to that of the noncompetitive NMDA receptor antagonist MK801. These data provide in vivo proof‐of‐concept of the neuroprotective effects of reversible caspase‐3 inhibitors in a model of malonate‐induced striatal injury in the adult rat.

Discovery of [(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonic acid, a potent and orally active small molecule PTP1B inhibitor

A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer.

Synthesis of benzylic boronates via palladium-catalyzed cross-coupling reaction of bis(pinacolato)diboron with benzylic halides

The palladium cross-coupling reaction of benzyl halides with diboron 1 yielded structurally diverse pinacol benzylic boronates. Under these reaction conditions, sensitive functionalities such as esters and nitriles are tolerated and the benzylic boronates are obtained in good to high yields.

Synthesis of phenylacetic acids under rhodium-catalyzed carbonylation conditions

Abstract Benzyl halides are efficiently carbonylated to phenylacetic acids in the presence of a catalytic amount of the dimer of chloro(1,5-cyclooctadiene)rhodium(I) in formic acid. Under these reaction conditions, sensitive functionalities such as esters and nitriles are tolerated and the phenylacetic acids are obtained in good to high yields.

Silyloxy-cope rearrangement of chiral aldol adducts

Abstract The silyloxy-Cope rearrangement of a chiral 1,5-diene generated from aldol condensation proceeds in high yield and selectivity under mild thermal conditions to generate a new stereocenter five atoms removed from the chiral auxiliary.

Solid phase parallel synthesis of highly substituted thiophene derivatives and identification of novel phosphodiesterase-4 (PDE-4) inhibitors

Abstract A versatile protocol for solid phase synthesis of highly substituted thiophene derivatives and their activity against the PDE-4 enzyme are discussed. This protocol employs 3-hydroxymethylthiophene-2-boronic acid (5) as the scaffold and sequential palladium catalyzed cross-coupling reactions as the CC bond forming step. This methodology allows convenient modification of the thiophene core from three directions, giving rise to structurally diverse derivatives with overall high chemical purity and yield. A novel series of potent PDE-4 inhibitors have been identified from these compounds.

Trisubstituted ureas as potent and selective mPGES-1 inhibitors

A novel series of trisubstituted ureas has been identified as potent and selective mPGES-1 inhibitors. These compounds are selective over other prostanoid enzymes such as PGF synthase and TX synthase. This series of inhibitors was developed by lead optimization of a hit from an internal HTS campaign. Lead compound 42 is potent in A549 cell assay (IC(50) of 0.34 μM) and in human whole blood assay (IC(50) of 2.1 μM). An efficient and versatile one-pot strategy for the formation of ureas, involving a reductive amination, was developed to generate these inhibitors.