Benzoylalanine-Derived Ketoamides Carrying Vinylbenzyl Amino Residues:  Discovery of Potent Water-Soluble Calpain Inhibitors with Oral Bioavailability

• Published in: Journal of medicinal chemistry 2003-06, Vol.46 (12), p.2404-2412
• Main Authors: Lubisch, Wilfried, Beckenbach, Edith, Bopp, Sabina, Hofmann, Hans-Peter, Kartal, Arzu, Kästel, Claudia, Lindner, Tanja, Metz-Garrecht, Marion, Reeb, Jutta, Regner, Ferdinand, Vierling, Michael, Möller, Achim
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - pharmacokinetics; Alanine - pharmacology; Animals; Benzene Derivatives - chemical synthesis; Benzene Derivatives - pharmacokinetics; Benzene Derivatives - pharmacology; Biological and medical sciences; Biological Availability; Blood Platelets - drug effects; Blood Platelets - metabolism; Brain Injuries - drug therapy; Brain Injuries - pathology; Calpain - antagonists & inhibitors; Cell Survival - drug effects; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - pharmacokinetics; Cysteine Proteinase Inhibitors - pharmacology; Dentate Gyrus - drug effects; Dentate Gyrus - pathology; Humans; In Vitro Techniques; Male; Medical sciences; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - pharmacology; Pharmacology. Drug treatments; Proto-Oncogene Proteins pp60(c-src) - metabolism; Rats; Rats, Sprague-Dawley; Solubility; Stereoisomerism; Structure-Activity Relationship; Vinyl Compounds - chemical synthesis; Vinyl Compounds - pharmacokinetics; Vinyl Compounds - pharmacology; Water
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0210717

Novel benzoylalanine-derived ketoamides were prepared and evaluated for calpain I inhibition. Derivatives carrying vinylbenzyl amino residues in the P2−P3 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.