title: Substituted 2,2-bisaryl-bicycloheptanes as novel and potent inhibitors of 5-lipoxygenase activating protein.
abstract: The discovery and SAR of a novel series of substituted 2,2-bisaryl-bicycloheptane inhibitors of 5-lipoxygenase activating protein (FLAP) are herein described. SAR studies have shown that 2,5-substitution on the exo-aryl group is optimal for potency. The most potent compounds in this series have an ortho-nitrogen aryl linked with a methyleneoxy as the 5-substituent and a polar group such as a urethane as the 2-substituent. One of the most potent compounds identified is the 5-benzothiazolymethoxy-2-pyridinylcarbamate derivative 2 (FLAP IC(50)=2.8 nM) which blocks 89% of ragweed induced urinary LTE(4) production in dogs (at an I.V. dose of 2.5 microg/kg/min). This compound inhibits calcium ionophore stimulated LTB(4) production in both human polymorphonuclear (PMN) leukocytes and human whole blood (IC(50)=2.0 and 33 nM, respectively).
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy., Kirkland, Que., Canada H9H 3L1. dwight_macdonald@merck.com
authors.forename: Dwight
authors.initials: D
authors.lastname: Macdonald
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Richard
authors.initials: R
authors.lastname: Frenette
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Guay
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
authors.forename: Hélène
authors.initials: H
authors.lastname: Perrier
authors.forename: Peptiboon
authors.initials: P
authors.lastname: Prasit
authors.forename: Denis
authors.initials: D
authors.lastname: Riendeau
authors.forename: Philip
authors.initials: P
authors.lastname: Tagari
authors.forename: Michel
authors.initials: M
authors.lastname: Thérien
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.forename: Yves
authors.initials: Y
authors.lastname: Girard
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D031164:Ambrosia / Q000737:chemistry; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D006536:Heptanes / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000378:metabolism; D017998:Leukotriene D4 / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D001643:Bridged Bicyclo Compounds; D002352:Carrier Proteins; D006536:Heptanes; D007211:Indoles; D007457:Iodine Radioisotopes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011804:Quinolines; C078266:MK 0591; C074616:L 691831; D017998:Leukotriene D4