Stereospecific Synthesis of Peptidyl .alpha.-Keto Amides as Inhibitors of Calpain

Peptidyl alpha-keto amides have been synthesized and tested as inhibitors of the cysteine protease calpain. A stereospecific synthesis was devised in which Cbz-dipeptidyl-alpha-hydroxy amides were oxidized with TEMPO/hypochlorite to the corresponding alpha-keto amides. This oxidation was accomplishe...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 37; no. 18; pp. 2918 - 2929
Main Authors:	Harbeson, Scott L, Abelleira, Susan M, Akiyama, Alan, Barrett, Robert, Carroll, Renee M, Straub, Julie Ann, Tkacz, Jaroslaw N, Wu, Chichih, Musso, Gary F
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-09-1994
Subjects:	Aliphatic compounds Amides - chemical synthesis Amides - pharmacology Amino Acid Sequence Animals Calpain - antagonists & inhibitors Cattle Chemistry Dipeptides - chemical synthesis Dipeptides - pharmacology Drug Stability Exact sciences and technology Humans In Vitro Techniques Ketones - chemical synthesis Ketones - pharmacology Molecular Sequence Data Oligopeptides - chemical synthesis Oligopeptides - pharmacology Organic chemistry Preparations and properties Solubility Stereoisomerism Structure-Activity Relationship Swine Ketoamide Enzyme Aliphatic compound Cysteine endopeptidases Hydroxyamide Enzyme inhibitor Calpain Biological activity Pseudopeptide Hydrolases Stereospecificity Oxidation Proteinases
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Summary:	Peptidyl alpha-keto amides have been synthesized and tested as inhibitors of the cysteine protease calpain. A stereospecific synthesis was devised in which Cbz-dipeptidyl-alpha-hydroxy amides were oxidized with TEMPO/hypochlorite to the corresponding alpha-keto amides. This oxidation was accomplished in good yields and without epimerization of the chiral center adjacent to the ketone. The potent inhibition of porcine calpain I by the L,L diastereomers, combined with the poor inhibition by the L,D diastereomers, established the requirement for the all-L stereochemistry of the active inhibitor. The early lead inhibitors were very hydrophobic and, therefore, poorly soluble in aqueous solutions. Using the stereospecific route, new compounds were prepared with polar groups at the C- and N-termini. These modifications resulted in more soluble inhibitors that were still potent inhibitors of calpain. Studies of the stability of these alpha-keto amides showed that absolute stereochemistry can be maintained in acidic and unbuffered environments but general base-catalyzed epimerization of the chiral center adjacent to the ketone occurred rapidly. The alpha-hydroxy precursors were inactive as inhibitors of calpain, which supports the hypothesis that the alpha-keto compounds reversibly form an enzyme-bound tetrahedral species that results from the nucleophilic addition of the catalytic thiol of calpain to the electrophilic ketone of the inhibitor.
Bibliography:	istex:FA4692979B09EBCB5588021ED15DE3F5A04D5E72 ark:/67375/TPS-MHPR31RG-C ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm00044a013