Leukotriene (LT) receptor antagonists. Heterocycle-linked tetrazoles and carboxylic acids. LY203647.
LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl] ethanone, is an orally active antagonist of LTD4- and LTE4-induced responses in a variety of test systems. We prepared a new series of LT antagonists based on a proposed model of LY171883 binding to the LTE4 receptor in which the n-propyl and tetrazole moieties of LY171883 occupy those parts of the receptor to which the C1-C5 chain and the cysteinyl carboxyl of LTE4 bind, respectively. The new compounds have an acidic function corresponding to the glycine carboxyl of LTD4 linked through a heterocyclic group which is proposed to bind to the LTD4 receptor where the cysteinyl glycine amide bond of LTD4 binds. LY203647, 1-[2-hydroxy-3-propyl-4-[4-[2-[4-(1H-tetrazol-5-yl)butyl]-2H- tetrazol-5-yl]butoxy]phenyl] ethanone, showed good LTD4 antagonist activity with a suitable pharmacologic and toxicologic profile and has been chosen for clinical evaluation.
Marshall
W S
WS
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Sigmund
S K
SK
Whitesitt
C A
CA
Lifer
S L
SL
Roman
C R
CR
Rinkema
L E
LE
Hahn
R A
RA
Fleisch
J H
JH
D000098:Acetophenones / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011971:Receptors, Immunologic / Q000378:metabolism; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
D000098:Acetophenones; D001393:Azoles; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013777:Tetrazoles; C061324:LY 203647; C044660:LY 171883