title: Small-molecular inhibitors of Ca²⁺-induced mitochondrial permeability transition (MPT) derived from muscle relaxant dantrolene.
abstract: A structure consisting of substituted hydantoin linked to a 5-(halophenyl)furan-2-yl group via an amide bond was identified as a promising scaffold for development of low-molecular-weight therapeutic agents to treat vascular dysfunction, including ischemia/reperfusion injury. Among the compounds synthesized, 5-(3,5-dichlorophenyl)-N-{2,4-dioxo-3-[(pyridin-3-yl)methyl]imidazolidin-1-yl}-2-furamide (17) possessed the most potent inhibitory activity against Ca(2+)-induced mitochondrial swelling. The structural development, synthesis and structure-activity relationship of these compounds are described.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Shinpei
authors.initials: S
authors.lastname: Murasawa
authors.forename: Katsuya
authors.initials: K
authors.lastname: Iuchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
authors.forename: Tomomi
authors.initials: T
authors.lastname: Noguchi-Yachide
authors.forename: Mikiko
authors.initials: M
authors.lastname: Sodeoka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yokomatsu
authors.forename: Kosuke
authors.initials: K
authors.lastname: Dodo
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aoyama
mesh_terms: D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D016572:Cyclosporine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003524:Cyclosporins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003620:Dantrolene / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D009126:Muscle Relaxation / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D003524:Cyclosporins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D054852:Small Molecule Libraries; D016572:Cyclosporine; C050026:cyclosporin D; D003620:Dantrolene; D002118:Calcium