A new series of 6-chloro-2,3-dihydro-4(1H)-quinazolinone derivatives as antiemetic and gastrointestinal motility enhancing agents.
New 6-chloro-2,3-dihydro-4(1H)-quinazolinones (24-27) have been synthesized and evaluated for gastrointestinal prokinetic and antiemetic activities in comparison with structurally related benzamides (21-22) and 6-chloro-2,3-dihydro-(1H)-1,3-benzoxazolin-4-ones (28). Their key pharmacophoric element has been defined as a 6-membered ring replacing the "virtual ring" arising from the hydrogen bond between amidic nitrogen and methoxy group in metoclopramide (1) and structurally related benzamides (2-10). Variations of heterocycle linking groups have pointed out that a lipophilic aromatic group in position 1 plays an important role for pharmacological properties, while the steric restriction and the modification of the side-chain nucleophilicity are uneffective both for the in vitro and in vivo activity. Some of these compounds very effectively enhance gut peristaltic activity in vitro (rabbit jejunum), increase gastric emptying of a semisolid meal (in rats), and inhibit cisplatin-induced emesis (in pigeons), favourably comparing with cisapride.
Baldazzi
C
C
Department of Biomedical Sciences, University of Modena, Italy.
Barbanti
M
M
Basaglia
R
R
Benelli
A
A
Bertolini
A
A
Piani
S
S
D000818:Animals; D000932:Antiemetics / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002945:Cisplatin / Q000037:antagonists & inhibitors; D010856:Columbidae; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects*; D066298:In Vitro Techniques; D007583:Jejunum / Q000187:drug effects; D008297:Male; D051379:Mice; D010528:Peristalsis / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
D000932:Antiemetics; D011799:Quinazolines; D002945:Cisplatin