N-[(arylmethoxy)phenyl] carboxylic acids, hydroxamic acids, tetrazoles, and sulfonyl carboxamides. Potent orally active leukotriene D4 antagonists of novel structure.
Four series of N-[(arylmethoxy)phenyl] compounds were prepared as leukotriene D4 (LTD4) antagonists. In the hydroxamic acid series, methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamate (Wy-48,422, 20) was the most potent inhibitor of LTD4-induced bronchoconstriction with an oral ED50 of 7.9 mg/kg. Compound 20 also orally inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ED50 of 3.6 mg/kg. In vitro, against LTD4-induced contraction of isolated guinea pig trachea pretreated with indomethacin and 1-cysteine, 20 produced a pKB value of 6.08. In the sulfonyl carboxamide series, N-[(4-methylphenyl)sulfonyl]-3-(2-quinolinylmethoxy)-benzamide (Wy-49,353, 30) was the most potent antagonist. Compound 30 orally inhibited both LTD4- and ovalbumin-induced bronchoconstriction with ED50s of 0.4 and 20.2 mg/kg, respectively. In vitro, against LTD4-induced contraction of isolated guinea pig trachea, 30 produced a pKB value of 7.78. In the carboxylic acid series, which served as intermediates for the above two series, 3-(2-quinolinylmethoxy)benzeneacetic acid (Wy-46,016, 5) was the most potent inhibitor of LTD4-induced bronchoconstriction (99% at 25 mg/kg, intraduodenally); however, the pKB for this compound was disappointing (5.79). In the tetrazole series, the most potent inhibitor was 2-[[3-(1H-tetrazol-5-ylmethyl)phenoxy]methyl]quinoline (Wy-49,451, 41). The respective inhibitory ED50s were 3.0 mg/kg versus LTD4 and 17.5 mg/kg versus ovalbumin. In the isolated guinea pig trachea, 41 produced a pKB value of 6.70.
Musser
J H
JH
Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Kreft
A F
AF
Bender
R H
RH
Kubrak
D M
DM
Grimes
D
D
Carlson
R P
RP
Hand
J M
JM
Chang
J
J
D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001681:Biological Assay; D001986:Bronchial Spasm / Q000139:chemically induced / Q000188:drug therapy; D002351:Carrageenan; D055598:Chemical Phenomena; D002621:Chemistry; D016861:Cyclooxygenase Inhibitors; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006168:Guinea Pigs; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010047:Ovalbumin; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D014132:Trachea / Q000187:drug effects
D001393:Azoles; D001549:Benzamides; D016861:Cyclooxygenase Inhibitors; D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D013189:SRS-A; D013777:Tetrazoles; C062498:3-(2-quinolinylmethoxy)benzeneacetic acid; C062444:methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamate; C062445:N-((4-methylphenyl)sulfonyl)-3-(2-quinolinylmethoxy)benzamide; C062446:WY 49451; D002351:Carrageenan; D010047:Ovalbumin