(Phenylmethoxy)phenyl derivatives of omega-oxo- and omega-tetrazolylalkanoic acids and related tetrazoles. Synthesis and evaluation as leukotriene D4 receptor antagonists.
Two series of (phenylmethoxy)phenyl compounds derived from the structure of LY163443 were synthesized and evaluated as leukotriene D4 receptor antagonists. In the omega-[(phenylmethoxy)phenyl]-omega-oxoalkanoic acid series, 5-[4-[(4-acetyl-2-ethyl-3-hydroxyphenyl)methoxy]phenyl]-3,3-dimethyl-5- oxopentanoic acid (8) was the most potent antagonist of LTD4-induced contractions of guinea pig ileum (pKB of 7.60) and LTD4 pressor response in pithed rats (ED50 of 1.4 mg/kg iv). Replacing the carboxylic acid function with 5-tetrazole gave slightly more potent compounds. In the omega-[5-[[(phenylmethoxy)phenyl]alkyl] tetrazolyl]alkanoic acid series, replacing the carboxylic acid with 5-tetrazole gave compounds that were equally effective in the guinea pig ileum but more potent in vivo against the LTD4 pressor response in rat. The pKB value in the guinea pig ileum for 1-[2-hydroxy-3-propyl-4- [[4-[[2-[3-(1H-tetrazol-5-yl)propyl]-2H-tetrazol-5-yl]methyl ] phenoxy]methyl]phenyl]ethanone (25) was 7.87 and the ED50 for antagonism of the LTD4 pressor response was 4.0 mg/kg iv. The sodium salts of 8 (9) and 25 (26) given by the iv route of administration antagonized LTD4-induced cardiovascular alterations in anesthetized rat and LTD4-induced bronchoconstriction in guinea pig in a dose-dependent manner. Oral activity was also demonstrated against the LTD4-induced bronchoconstriction in guinea pig.
Dillard
R D
RD
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Hahn
R A
RA
McCullough
D
D
Carr
F P
FP
Rinkema
L E
LE
Roman
C R
CR
Fleisch
J H
JH
D000098:Acetophenones / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000378:metabolism*; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D000098:Acetophenones; D002264:Carboxylic Acids; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013777:Tetrazoles; C049043:LY 163443