title: Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo.
abstract: In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.
authors.affiliation: Genextra Group, Congenia s.r.l. , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Fancelli
authors.forename: Agnese
authors.initials: A
authors.lastname: Abate
authors.forename: Raffaella
authors.initials: R
authors.lastname: Amici
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Marco
authors.initials: M
authors.lastname: Ballarini
authors.forename: Anna
authors.initials: A
authors.lastname: Cappa
authors.forename: Giacomo
authors.initials: G
authors.lastname: Carenzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Colombo
authors.forename: Cristina
authors.initials: C
authors.lastname: Contursi
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Lisa
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.forename: Stefania
authors.initials: S
authors.lastname: Gagliardi
authors.forename: Eva
authors.initials: E
authors.lastname: Milanesi
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Gilles
authors.initials: G
authors.lastname: Pain
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Alessandra
authors.initials: A
authors.lastname: Saccani
authors.forename: Mariangela
authors.initials: M
authors.lastname: Storto
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Manuela
authors.initials: M
authors.lastname: Villa
authors.forename: Simon
authors.initials: S
authors.lastname: Plyte
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000591352:3-(4-fluoro-3-hydroxyphenyl)-N-naphthalen-1-yl-acrylamide; D000178:Acrylamides; D000813:Anilides; D002934:Cinnamates; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015057:1-Naphthylamine; D002118:Calcium