Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.

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Khanapure SP, Garvey DS, Young DV, Ezawa M, Earl RA, Gaston RD, Fang X, Murty M, Martino A, Shumway M, Trocha M, Marek P, Tam SW, Janero DR, Letts LG

Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.

J Med Chem. 2003 Dec 4;46(25):5484-504.

PubMed ID

14640557 [ View in PubMed

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Abstract

A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC(50) for 22c = 1 microM and COX-1 IC(50) for 22c = 20 microM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 microM in an in vitro HWB assay.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Celecoxib	Prostaglandin G/H synthase 2	IC 50 (nM)	54	N/A	N/A	Details
Celecoxib	Prostaglandin G/H synthase 2	IC 50 (nM)	1200	N/A	N/A	Details
Rofecoxib	Prostaglandin G/H synthase 2	IC 50 (nM)	1000	N/A	N/A	Details
Rofecoxib	Prostaglandin G/H synthase 2	IC 50 (nM)	300	N/A	N/A	Details