Jacques-Yves Gauthier

The discovery of rofecoxib, [MK 966, VIOXX®, 4-(4′-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2 inhibitor

The development of a COX-2 inhibitor rofecoxib (MK 966, Vioxx) is described. It is essentially equipotent to indomethacin both in vitro and in vivo but without the ulcerogenic side effect due to COX-1 inhibition.

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.

Cathepsin K inhibitors prevent bone loss in estrogen‐deficient rabbits

Two cathepsin K inhibitors (CatKIs) were compared with alendronate (ALN) for their effects on bone resorption and formation in ovariectomized (OVX) rabbits. The OVX model was validated by demonstrating significant loss (9.8% to 12.8%) in lumbar vertebral bone mineral density (LV BMD) in rabbits at 13‐weeks after surgery, which was prevented by estrogen or ALN. A potent CatKI, L‐006235 (L‐235), dosed at 10 mg/kg per day for 27 weeks, significantly decreased LV BMD loss (p < .01) versus OVX‐vehicle control. ALN reduced spine cancellous mineralizing surface by 70%, whereas L‐235 had no effect. Similarly, endocortical bone‐formation rate and the number of double‐labeled Haversian canals in the femoral diaphysis were not affected by L‐235. To confirm the sparing effects of CatKI on bone formation, odanacatib (ODN) was dosed in food to achieve steady‐state exposures of 4 or 9 µM/day in OVX rabbits for 27 weeks. ODN at both doses prevented LV BMD loss (p < .05 and p < .001, respectively) versus OVX‐vehicle control to levels comparable with sham or ALN. ODN also dose‐dependently increased BMD at the proximal femur, femoral neck, and trochanter. Similar to L‐235, ODN did not reduce bone formation at any bone sites studied. The positive and highly correlative relationship of peak load to bone mineral content in the central femur and spine suggested that ODN treatment preserved normal biomechanical properties of relevant skeletal sites. Although CatKIs had similar efficacy to ALN in preventing bone loss in adult OVX rabbits, this novel class of antiresorptives differs from ALN by sparing bone formation, potentially via uncoupling bone formation from resorption.

Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enxyme induction

Abstract Structure-activity studies leading to the discovery of 1 (MK-0476) are described. The initial compound of this series, 2, was a potent leukotriene D4 (LTD4) antagonist, but was also a peroxisomal enzyme inducer in the mouse. Structure-activity relationships around the thioether chain were explored to remove this undesirable feature. It was found that alkyl substituents in the s position relative to the carboxylic acid reduce the potency as a peroxisomal enzyme inducer while preserving the LTD4 antagonistic properties. Dialkyl substitution essentially eliminates the enzyme induction. The optimal styryl quinoline 1 exhibited high in vitro potency and in vivo activity on oral dosing without significant liver enzyme induction in the mouse.

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.

SYNTHESIS AND BIOLOGICAL EVALUATION OF 2,3-DIARYLTHIOPHENES AS SELECTIVE COX-2 AND COX-1 INHIBITORS

Abstract A series of 2,3-diarylthiophene compounds was prepared and their biological activities were evaluated against human Cox-1 and Cox-2 enzymes. It appears that the methylsulfone group is essential for both the activity and selectivity for the Cox-2 enzyme. Removal of the methylsulfone group gave relatively selective Cox-1 inhibitors.

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.

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.

From Indomethacin to a Selective Cox-2 Inhibitor

It has been known since the early 1970’s that nonsteroidal antiinflammatory drugs (NSAIDs) exert their antinflammatory effects through the blocking of the synthesis of prostaglandins (PGs) by inhibiting cyclooxygenase (COX).1 Cyclooxygenase was believed to be a single enzyme present constitutively in many tissues. It is believed to be involved in the maintenance of essential physiological function such as platelet aggregation, cytoprotection in the stomach and maintenance of normal kidney function. While inhibiting the production of proinflammatory prostaglandins at the inflammatory sites, NSAIDs also reduce the cytoprotective PGs in the gastrointestinal (GI) tract, leading to mechanism-based GI toxicity.2 The recent discovery of an inducible isoform of cyclooxygenase (COX-2) that is associated primarily with inflammation3–5 has led to the hypothesis that NSAID-in-duced toxicity in the GI tract may be caused by the inhibition of the beneficial constitutive isoform of cyclooxygenase (COX-1) in these tissues, while the antiinflammatory effect of NSAIDs is due to the inhibition of the inducible isoform (COX-2) at the inflammation site. A selective COX-2 inhibitor has the potential therefore to be an effective antiinflammatory drug with reduced GI toxicity compared to current NSAIDs.

A series of non-quinoline cysLT1 receptor antagonists: SAR study on pyridyl analogs of Singulair

The structure-activity relationship of a series of styrylpyridine analogs of MK-0476 (montelukast, Singulair) is described. This work has led to the identification of a number of potent and orally active cysLT1 receptor (LTD4 receptor) antagonists including 2ab (L-733,321) as an optimized candidate.