3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles, a novel series of platelet activating factor antagonists.
(2RS,4R)-3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles represent a new class of potent, orally active antagonists of platelet activating factor (PAF). The compounds were prepared by acylation of the magnesium or zinc salts of substituted indoles with (2RS,4R)-2-(3-pyridinyl)-3-(tert-butoxycarbonyl)thiazolidin-4-oyl chloride. The 3-acylindole moiety functions as a hydrolytically stabilized and conformationally restricted anilide replacement, which imparts a considerable boost in potency to the series. Structure-activity relationships observed for substitution on the indole ring system are discussed. Members of the series compare favorably with other reported PAF antagonists.
Sheppard
G S
GS
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Pireh
D
D
Carrera
G M
GM
Bures
M G
MG
Heyman
H R
HR
Steinman
D H
DH
Davidsen
S K
SK
Phillips
J G
JG
Guinn
D E
DE
May
P D
PD
D000284:Administration, Oral; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000097:blood; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
D007211:Indoles; D010972:Platelet Activating Factor; D013844:Thiazoles; D012701:Serotonin