Prolyl endopeptidase inhibitor

Isocyanides, formal divalent carbon functionalities, are ideal candidates for the development of MCRs. Their reaction with carbonyls and imines, through an a-addition process, generates a zwitterionic intermediate, which is then trapped by a nucleophile. The resulting double a-addition adduct is unstable and rapidly undergoes the Mumm rearrangement to afford the final product (Scheme 12.32). The venerable three-component Passerini reaction is the first MCR based on this type of reaction process [116]. It addresses the formation of a-acyloxycarboxamides, which constitute a class of very versatile synthons in organic chemistry. In the present context, this reaction was utilized by Schmidt and collaborators for the elaboration of intermediate 234 [117], a key fragment for the synthesis of the prolyl endopeptidase inhibitor Eurystatin A 231 (Scheme 12.33) [118]. 

Owens, T. D., Araldi, G. L., Nutt, R. F., Semple, J. E. Concise total synthesis of the prolyl endopeptidase inhibitor eurystatin A via a novel Passerini reaction-deprotection-acyl migration strategy. Tetrahedron Lett. 2001,42, 6271-6274. 

R635 K. Kanai, M. Feher, A. Lopata, B. Podanyi, I. Novik, E. Susan, I. Hermecz and P. Aranyi, Molecular Modeling and CoMFA Studies on Prolyl Endopeptidase Inhibitors , Acta Pharm. Hung., 1999, 69, 240 R636 L. Toke, Supramolecular Chemistry, Crown Ethers , Magy. Kem. Foly., 2000,106, 111... 

Cyclic peptide antibiotic. Prod, by Microbispora sp. Prolyl endopeptidase inhibitor. Mp 230-240°. [a] —87. 

T. C. Friedman, S. Wilk, The Effect of Inhibitors of Prolyl Endopeptidase and Pyro-glutamyl Pephde Hydrolase on TRH Degradation in Rat Serum , Biochem. Biophys. Res. Commun. 1985, 132, 787-794. 

The title compound, 2-(8-dimethylaminooctylthio)-6-isopropyl-3-pirydyl-2-thienyl ketone (222), a potent competitive reversible inhibitor of the enzyme PEP (prolyl endopeptidase which cleaves a variety of oligopeptides in brain and peripheral tissues217), has been synthesized218 by ["CJalkylation of the iV-desmethyl precursor 223 (equation 117). 222 crosses the BBB and inhibits brain PEP in rodents219. It is used in the study of biodistribution and activity of brain proteases by PET to evaluate the roles... 

Poststatin, H-Val-Val-Pos-D-Leu-Val-OH, a naturally occurring 5-peptide isolated from Streptomyces viridochromogenes. It acts as an inhibitor of prolyl endopeptidase. Pos is the abbreviation for (S)-3-amino-2-oxopentanoic acid, named L-postine. The a-keto-amide group seems to be necessary for the biological activity [M. Tsuda et al., J. Antibiot.(Tokyo) 1996, 49, 1022 H. H. Wassermann, A. K. Petersen, Tetrahedron Lett. 1997, 38, 953]. 

The prolyl endopeptidase (PEP) inhibitor eurystatin A has been synthesized by two distinct strategies that incorporated the P-3CR. A particularly efficient approach used protected ornithine 60 as the carboxylic... 

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