title: Benzoylalanine-derived ketoamides carrying vinylbenzyl amino residues: discovery of potent water-soluble calpain inhibitors with oral bioavailability.
abstract: Novel benzoylalanine-derived ketoamides were prepared and evaluated for calpain I inhibition. Derivatives carrying vinylbenzyl amino residues in the P(2)-P(3) region inhibited calpain in nanomolar concentrations and thus represent a novel class of nonpeptidic calpain inhibitors. Selected examples exhibited an improved pharmacokinetic profile including improved water-solubility and metabolic stability. In particular, these calpain inhibitors showed oral bioavailability in rats as demonstrated by N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethylaminomethylphenyl)ethen-1-yl]benzamide (5d). The closely related derivative N-(1-carbamoyl-1-oxohex-1-yl)-2-[E-2-(4-dimethylaminomethylphenyl)-ethen-1-yl]benzamide (5b) was evaluated for neuroprotective efficacy after experimental traumatic brain injury in a fluid percussion model in rats. When administered after injury, 5b reduced the number of damaged neurons by 41%, and this result would be in line with the suggested neuroprotective efficacy of calpain inhibition.
authors.affiliation: Neuroscience Discovery Research, Abbott GmbH & Co. KG, P.O. Box 210805, D-67008 Ludwigshafen, Germany. wilfried.lubisch@abbott.com
authors.forename: Wilfried
authors.initials: W
authors.lastname: Lubisch
authors.forename: Edith
authors.initials: E
authors.lastname: Beckenbach
authors.forename: Sabina
authors.initials: S
authors.lastname: Bopp
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hofmann
authors.forename: Arzu
authors.initials: A
authors.lastname: Kartal
authors.forename: Claudia
authors.initials: C
authors.lastname: Kästel
authors.forename: Tanja
authors.initials: T
authors.lastname: Lindner
authors.forename: Marion
authors.initials: M
authors.lastname: Metz-Garrecht
authors.forename: Jutta
authors.initials: J
authors.lastname: Reeb
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Regner
authors.forename: Michael
authors.initials: M
authors.lastname: Vierling
authors.forename: Achim
authors.initials: A
authors.lastname: Möller
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014867:Water
chemical_list: D001555:Benzene Derivatives; D015853:Cysteine Proteinase Inhibitors; D018696:Neuroprotective Agents; D014753:Vinyl Compounds; D014867:Water; D016392:Proto-Oncogene Proteins pp60(c-src); D002154:Calpain; D000409:Alanine