title: Design, synthesis and quantitative structure-activity relationship study of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidine derivatives as potent Na/H exchange inhibitors.
abstract: Inhibition of the Na/H exchanger is a promising approach for treating ischemia-reperfusion injury, but no clinical agent is yet available. Recently, we established the structural requirements for potent inhibitors of the Na/H exchanger. In the present work, we designed N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidine 3a as a new lead compound for potent inhibitors with good water-solubility, based on the previous information. During the structural optimization, care was taken to keep the hydrophobicity (clogP) in the range of about 1.5-2.0, which is considered optimum for good bioavailability. Various derivatives of 3a were synthesized and the quantitative structure-activity relationship (QSAR) was studied. The QSAR result indicated that the lengths of the substituents at the 2- and the 4-positions of the 2H-benzo[1,4]oxazine ring are parabolically related to activity. The most potent compounds were (R) and/or (S)-N-(2-ethyl-4-isopropyl(or ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidines 3q-t with IC50 values of 0.036-0.073 microM. The water-solubility of the hydrochlorides and methanesulfonates is 3-5 mg/ml, which is sufficient for therapeutic use.
authors.affiliation: Product R & D Laboratory, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Hori
authors.forename: I
authors.initials: I
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Tsutsui
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: J
authors.initials: J
authors.lastname: Maruo
authors.forename: T
authors.initials: T
authors.lastname: Morita
authors.forename: H
authors.initials: H
authors.lastname: Ohtaka
mesh_terms: D000818:Animals; D015195:Drug Design; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; C110561:N-(2,4-diethyl-3-oxo-3,4-dihydro-2H-benzo(1,4)oxazine-7-carbonyl)guanidine; C110560:N-(2-ethyl-4-isopropyl-3-oxo-3,4-dihydro-2H-benzo(1,4)oxazine-7-carbonyl)guanidine; D010078:Oxazines; D010975:Platelet Aggregation Inhibitors; D017923:Sodium-Hydrogen Exchangers