Stereospecific synthesis, assignment of absolute configuration, and biological activity of the enantiomers of 3-[[[3-[2-(7-chloroquinolin-2-yl)-(E)-ethenyl]phenyl] [[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid, a potent and specific leukotriene D4 receptor antagonist.
The enantiomers of the leukotriene D4 antagonist 3-[[[3-[2-(7-chloroquinolin-2-yl)-(E)-ethenyl]phenyl] [[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid (L-660,711)(MK-571) have been prepared, their absolute stereochemistry has been assigned as S for (+)-1 and R for (-)-1 by X-ray analysis of a synthetic intermediate (5), and the biological activity of the enantiomers has been explored. Unexpectedly, the enantiomers are both comparably biologically active with (+)-1 slightly more intrinsically active at the LTD4 receptor in vitro.
Gauthier
J Y
JY
Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
Jones
T
T
Champion
E
E
Charette
L
L
Dehaven
R
R
Ford-Hutchinson
A W
AW
Hoogsteen
K
K
Lord
A
A
Masson
P
P
Piechuta
H
H
D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008968:Molecular Conformation; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011422:Propionates; D011804:Quinolines; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C059141:verlukast