Patrick Roy

FROM INDOMETHACIN TO A SELECTIVE COX-2 INHIBITOR Development of Indolalkanoic Acids as Potent and Selective Cyclooxygenase-2 Inhibitors

Abstract A series of potent and highly selective cyclooxygenase-2 inhibitors have been prepared by replacing the benzoyl group of indomethacin with a 4-bromobenzyl group, and by extending the acetic acid side chain. These compounds show anti-inflammatory activity in rats with no evidence of GI toxicity, even at high doses.

Synthesis and biological evaluation of 5,6-diarylimidazo[2.1-b]thiazole as selective COX-2 inhibitors

Abstract A series of 5,6-diarylimidazo[2.1-b]thiazole compounds were prepared and their inhibitory potencies against COX-2 and Cox-1 enzymes were measured. This led to the identification of L-766,112 as a potent, orally active and selective inhibitor of the COX-2 enzyme.

A new series of selective COX-2 inhibitors: 5,6-diarylthiazolo[3,2-b][1,2,4]triazoles

A series of 5,6-diarylthiazolo[3,2-b][1,2,4]triazoles was prepared for evaluation of potency and selectivity against human COX-1 and COX-2 enzymes. This lead to the discovery of L-768,277, a potent and selective COX-2 inhibitor that also demonstrated good in vivo activity.

SAR in the alkoxy lactone series: the discovery of DFP, a potent and orally active COX-2 inhibitor.

Extensive SAR has been established in the alkoxy lactone series and this has lead to the discovery of DFP (5,5-dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanon e), a potent COX-2 inhibitor exhibiting in vivo efficacy in all models studied.

Synthesis, characterization, and activity of metabolites derived from the cyclooxygenase-2 inhibitor rofecoxib (MK-0966, Vioxx)

Metabolites of the COX-2 inhibitor rofecoxib (MK-0966, Vioxx) were prepared by synthetic or biosynthetic methods. Metabolites include products of oxidation, glucuronidation, reduction and hydrolytic ring opening. Based on an in vitro whole blood assay, none of the known human metabolites of rofecoxib inhibits COX-1 nor contributes significantly to the inhibition of COX-2.

SYNTHESIS AND BIOLOGICAL EVALUATION OF BOTH ENANTIOMERS OF L-761,000 AS INHIBITORS OF CYCLOOXYGENASE 1 AND 2

Abstract Both enantiomers of L-761,000 were prepared and evaluated for their cyclooxygenase activities.

Identification of prostaglandin D2 receptor antagonists based on a tetrahydropyridoindole scaffold.

A new series of indole-based antagonists of the PGD(2) receptor subtype 1 (DP1 receptor) was identified and the progress of the structure-activity relationship study to the identification of potent and selective antagonists is presented. Selective DP1 antagonists with high potency and selectivity were prepared. Of particular interest is the DP1 antagonist 26 with a K(i) value of 1 nM for the DP1 receptor and an IC(50) value of 4.6 nM in a DP1 functional assay for the inhibition of the PGD(2) induced cAMP production in platelet rich plasma (PRP).

The discovery of a new structural class of potent orally active leukotriene D4 antagonists

Abstract A new, potent, orally active leukotriene D 4 receptor antagonist has been discovered. The structure -activity relationship leading to L-695,499 is described.

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.

Discovery of a potent and selective COX-2 inhibitor in the alkoxy lactone series with optimized metabolic profile.

The COX-2 inhibitor DFP [5,5-dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone] was found to have a long half-life in humans. Analogues have been characterized in order to optimize pharmacokinetics. This has lead to the discovery of 5(S)-(5-ethyl-5-methyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone analogue 11 a potent and selective COX-2 inhibitor which is metabolized to a greater extent than DFP upon incubation with rat and human hepatocytes, suggesting a shorter half-life in humans.