title: Synthesis and activity against multidrug resistance in Chinese hamster ovary cells of new acridone-4-carboxamides.
abstract: A number of tricyclic carboxamides have been synthesized and tested to evaluate their ability to reverse multidrug resistance in the CHRC/5 cell line. Among them the acridone derivatives were the most potent. A key feature is the presence of a dimethoxybenzyl or phenethylamine cationic site, separated from the tricyclic lipophilic part by a carbamoylphenyl chain. Optimization led to compounds 2 orders of magnitude more active than the prototype inhibitors verapamil and amiodarone. On the basis of in vitro and in vivo activities, 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7- dimethoxyisoquinol-2-yl)ethyl]phenyl]-4-acridinecarboxamide (84) has been selected for further development.
authors.affiliation: Laboratories Glaxo Centre de Recherches, ZA de Courtaboeuf, Les Ulis, France.
authors.forename: N
authors.initials: N
authors.lastname: Dodic
authors.forename: B
authors.initials: B
authors.lastname: Dumaitre
authors.forename: A
authors.initials: A
authors.lastname: Daugan
authors.forename: P
authors.initials: P
authors.lastname: Pianetti
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018432:Drug Resistance, Multiple; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; C071880:9(10H)-acridone carboxamide