The synthesis of ketomethylene pseudopeptide analogues of dipeptide aldehyde inhibitors of calpain

• Published in: Bioorganic & medicinal chemistry letters 1999-01, Vol.9 (2), p.139-140
• Main Authors: Angelastro, Michael R., Marquart, Angela L., Mehdi, Shujaath, Koehl, Jack R., Vaz, Roy J., Bey, Philippe, Peet, Norton P.
• Format: Article
• Language: English
• Subjects: Aldehydes - chemistry; Aliphatic compounds; Animals; Biological and medical sciences; Calpain - antagonists & inhibitors; Calpain - chemistry; Chemistry; Chickens; Exact sciences and technology; Gizzard, Avian - chemistry; Ketones - chemistry; Medical sciences; Muscle, Smooth - chemistry; Neuropharmacology; Neuroprotective agent; Organic chemistry; Peptide Fragments - chemistry; Pharmacology. Drug treatments; Preparations and properties
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(98)00704-5

The ketomethylene phenylalanal and alanal analogues of Cbz-Val-Phe-H and Cbz-Val-Ala-H have been prepared and the K i values versus chicken gizzard smooth muscle calpain were determined. The ketomethylene isosteres were significantly less potent than the corresponding dipeptide aldehydes, and this loss in activity is attributed to the absence of a critical interaction between the P1–P2 amide bond and the peptide binding region of calpain. The ketomethylene phenylalanal and alanal analogues of Cbz-Val-Phe-H and Cbz-Val-Ala-H have been prepared from α-methylene-γ-butyrolactone 4. The subsequent arylation, reduction, and bis-Swern oxidation generated the targeted γ-ketoaldehyde 9.