Substituted 2,2-bisaryl-bicycloheptanes as novel and potent inhibitors of 5-lipoxygenase activating protein.
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).
Macdonald
Dwight
D
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy., Kirkland, Que., Canada H9H 3L1. dwight_macdonald@merck.com
Brideau
Christine
C
Chan
Chi Chung
CC
Falgueyret
Jean-Pierre
JP
Frenette
Richard
R
Guay
Jocelyne
J
Hutchinson
John H
JH
Perrier
Hélène
H
Prasit
Peptiboon
P
Riendeau
Denis
D
Tagari
Philip
P
Thérien
Michel
M
Young
Robert N
RN
Girard
Yves
Y
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
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