title: Synthesis and biological evaluation of substituted benzenesulfonamides as novel potent membrane-bound phospholipase A2 inhibitors.
abstract: A novel series of 4-[N-methyl-N-[(E)-3-[4-(methylsulfonyl)phenyl]-2- propenoyl]amino]benzenesulfonamides has been prepared and evaluated as membrane-bound phospholipase A2 inhibitors. A structure-activity relationship study indicated that the optimum potency was realized with the N-(phenylalkyl)piperidine derivatives 3 and 4. These compounds inhibited the liberation of arachidonic acid from the rabbit heart membrane fraction with IC30 values of 0.028 and 0.009 microM, respectively. Several compounds (3, 4, and 28), which proved to be potent inhibitors in vitro, significantly reduced the size of myocardial infarction in coronary occluded rats by iv administrations prior to the ligation. N-(1-Benzyl-4-piperidinyl)-4-[N-methyl-N-[(E)-3-[ 4-(methylsulfonyl)phenyl]-2-propenoyl]amino]-benzenesulfonamide (3, ER-3826), which showed the protective in vivo effects at doses higher than 0.3 mg/kg iv, was finally chosen as a leading candidate.
authors.affiliation: Department of Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Oinuma
authors.forename: T
authors.initials: T
authors.lastname: Takamura
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
authors.forename: K
authors.initials: K
authors.lastname: Nomoto
authors.forename: T
authors.initials: T
authors.lastname: Naitoh
authors.forename: Y
authors.initials: Y
authors.lastname: Daiku
authors.forename: S
authors.initials: S
authors.lastname: Hamano
authors.forename: H
authors.initials: H
authors.lastname: Kakisawa
authors.forename: N
authors.initials: N
authors.lastname: Minami
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000627:therapeutic use; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology; D055598:Chemical Phenomena; D002621:Chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006321:Heart / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D010880:Piperidines / Q000138:chemical synthesis* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000627:therapeutic use; D000096926:Benzenesulfonamides
chemical_list: D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D010741:Phospholipases A; D054467:Phospholipases A2; D010880:Piperidines; D013449:Sulfonamides; C069796:ER 3826; D000096926:Benzenesulfonamides