Cheuk K. Lau

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.

Pyridazinones as selective cyclooxygenase-2 inhibitors.

Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and rat pyresis models, have been obtained.

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.

Synthesis and biological evaluation of 2,3-diarylthiophenes as selective cox-2 inhibitors. part II: Replacing the heterocycle

Abstract The thiophene ring of DuP 697 was replaced by a variety of heterocycles and the products were tested for their ability to inhibit human Cox-2 and Cox-1, the isozymes of cyclooxygenase.

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.

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.

Conformation-assisted Inhibition of Protein-tyrosine Phosphatase-1B Elicits Inhibitor Selectivity over T-cell Protein-tyrosine Phosphatase

PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.

Syntheses of quinolines, dihydro- and tetrahydroquinolines via ortho-quinone methide imine intermediate

Abstract A general process for ortho -specific hydroxyalkylation of secondary anilines via N-alkylanilinochlorophenylboranes has been developed. Pyrolysis of the resulting ortho -aminobenzyl alcohols generated the corresponding ortho -quinone methide imines, which can participate in an electrocyclic reaction to yield 2-substituted-1,2-dihydroquinolines. The resulting dihydroquinolines can be converted readily to a variety of 2-substituted quinolines. Intramolecular trapping of the ortho -quinone methide imines with an olefin via a [2+4] cycloaddition reaction leads to the syntheses of various polycyclic tetrahydroquinolines.

Synthesis and biological evaluation of 3-heteroaryloxy-4-phenyl-2(5H)-furanones as selective COX-2 inhibitors

A series of 3-heteroaryloxy4-phenyl-2-5H)-furanones were prepared and evaluated for their potency and selectivity as COX-2 inhibitors. This led to the identification of L-778,736 as a potent, orally active and selective inhibitor of the COX-2 enzyme.