title: Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.
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.
authors.affiliation: NitroMed, Inc, 12 Oak Park Drive, Bedford, Massachusetts 01730, USA. skhanapure@nitomed.com
authors.forename: Subhash P
authors.initials: SP
authors.lastname: Khanapure
authors.forename: David S
authors.initials: DS
authors.lastname: Garvey
authors.forename: Delano V
authors.initials: DV
authors.lastname: Young
authors.forename: Maiko
authors.initials: M
authors.lastname: Ezawa
authors.forename: Richard A
authors.initials: RA
authors.lastname: Earl
authors.forename: Rick D
authors.initials: RD
authors.lastname: Gaston
authors.forename: Xinqin
authors.initials: X
authors.lastname: Fang
authors.forename: Madhavi
authors.initials: M
authors.lastname: Murty
authors.forename: Allison
authors.initials: A
authors.lastname: Martino
authors.forename: Matthew
authors.initials: M
authors.lastname: Shumway
authors.forename: Mark
authors.initials: M
authors.lastname: Trocha
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Marek
authors.forename: S William
authors.initials: SW
authors.lastname: Tam
authors.forename: David R
authors.initials: DR
authors.lastname: Janero
authors.forename: L Gordon
authors.initials: LG
authors.lastname: Letts
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003516:Cycloparaffins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003516:Cycloparaffins; D004148:Dioxolanes; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases