Acrylamide derivatives as antiallergic agents. 2. Synthesis and structure-activity relationships of N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(3-pyridyl)acryl amides.
A new series of 3-(3-pyridyl)acrylamides 16, 17, 19, and 26, and 5-(3-pyridyl)-2,4-pentadienamides 20-25 were prepared and evaluated for their antiallergic activity. Several of these compounds exhibited more potent inhibitory activities than the parent compound 1a [(E)-N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3- (3-pyridyl)acrylamide] against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase. Particularly, (E)-N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3- (6-methyl-3-pyridyl)acrylamide (17p) showed an ED50 value of 3.3 mg/kg po in the rat PCA test, which was one-fifth of ketotifen and oxatomide. As compared with ketotifen and oxatomide, compound 17p (AL-3264) possessed a better balance of antiallergic properties due to inhibition of chemical mediator release, inhibition of 5-lipoxygenase, and antagonism of histamine.
Nishikawa
Y
Y
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Shindo
T
T
Ishii
K
K
Nakamura
H
H
Kon
T
T
Uno
H
H
D000178:Acrylamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy*; D066298:In Vitro Techniques; D007665:Ketotifen / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008297:Male; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000178:Acrylamides; D006633:Histamine Antagonists; D016859:Lipoxygenase Inhibitors; D010879:Piperazines; C015408:oxatomide; D007665:Ketotifen