Design, synthesis, and structure-activity relationship studies of 3,4,6-triphenylpyran-2-ones as selective cyclooxygenase-2 inhibitors.
A group of regioisomeric 3,4,6-triphenylpyran-2-ones with a MeSO(2) pharmacophore at the para-position of either a C-3 phenyl or a C-4 phenyl substituent on the central six-membered pyran-2-one ring were prepared and evaluated in vitro for their abilities to inhibit the isozymes COX-1 and COX-2. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position of the C-6 phenyl ring attached to the central pyranone, showed that 6-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was the most potent and selective COX-2 inhibitor (COX-2 IC(50) = 0.02 microM; COX-1 IC(50) > 100 microM) with a high COX-2 selectivity index (SI > 5000) relative to the reference drugs celecoxib (COX-2 IC(50) = 0.07 microM; SI = 474) and rofecoxib (COX-2 IC(50) = 0.50 microM; SI > 200). 6-(4-Methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was a more potent oral antiinflammatory agent (ID(50) = 5.6 mg/kg) than celecoxib (ID(50) = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. In a 4% NaCl-induced abdominal constriction assay, a 5 mg/kg oral dose of 12e exhibited good analgesic activity at different time intervals producing 37.5 and 69% inhibition of writhing at 30 and 60 min, respectively. In contrast, the corresponding 6-(4-methoxyphenyl)-4-(4-methanesulfonylphenyl)-3-phenylpyran-2-one regiosiomer (12o) was a less potent and selective COX-2 inhibitor (COX-2 IC(50) = 0.45 microM; SI = 70). A molecular modeling study for 12e indicated that the p-OMe substituent on the C-6 phenyl ring interacts with the COX-2 binding site amino acids Ile(345), Val(349), Leu(359), Leu(531), and Met(535) and that the OMe substituent may be responsible for proper orientation of the C-3 p-SO(2)Me-phenyl ring within the COX-2 secondary pocket (Gln(192), Arg(513), and Phe(518)). These results show that the COX-2 selectivity and potency of 3,4,6-triphenylpyranone regioisomers can be modulated by appropriate placement of the p-SO(2)Me pharmacophore on either the C-3 or C-4 phenyl moiety. In addition, electronic properties at the para-position of a C-6 phenyl substituent on the central pyranone ring govern COX-2 inhibitory potency and selectivity by controlling the orientation of the p-SO(2)Me pharmacophore within the COX-2 secondary pocket.
Rao
P N Praveen
PN
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8, Canada.
Uddin
Md Jashim
MJ
Knaus
Edward E
EE
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008565:Membrane Proteins; D008958:Models, Molecular; D010147:Pain Measurement / Q000379:methods; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C488670:6-(4-ethoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one; D000700:Analgesics; D007527:Isoenzymes; D008565:Membrane Proteins; D011714:Pyrans; D011753:Pyrones; D013450:Sulfones; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat