Discovery of phenyl alanine derived ketoamides carrying benzoyl residues as novel calpain inhibitors.
Novel calpain inhibitors derived from phenyl alanine aldehydes or ketoamides carrying a benzoyl residue were prepared and evaluated for their biological potency. A brief structure-activity relationship elucidated the importance of ortho-substitutents in the benzoyl moiety. The most potent derivative, the ketoamide 19c, exhibited a K(i) of 6nM and represents a novel class of reversible, highly potent and non-peptidic calpain inhibitors.
Lubisch
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Department of CNS Discovery Research, Abbott GmbH&Co. KG, PO Box 210805, 67008, Ludwigshafen, Germany. wilfried.lubish@abbott.com
Möller
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A
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000097:blood; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010649:Phenylalanine; D013329:Structure-Activity Relationship
D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D007651:Keto Acids; D010649:Phenylalanine; D002154:Calpain