Synthesis peptidase inhibitors

Summary of antimicrobial agents affecting cell wall synthesis [Note Cilastatin is not an antibiotic but a peptidase inhibitor that protects imipenem from degradation.]... 

Merck process research group developed a short and efficient synthesis of 3-(2,2,2-trifluoroethyl)-hexahydro-2//-l,4-diazepin-2-one 85 as part of an ongoing research program to identify peptidase inhibitors <07S2779>. 

During the last few years a large variety of highly sophisticated conformational constraints have been successfully applied to the design of peptidase inhibitors. Selected examples from the recent literature are summarized in Fig. 23.11. For instance, Veber and coworkers have recently described the design and synthesis of... 

As seen for the synthesis of statine, highly substituted hydroxy amino acids may be peptidase inhibitors. Several analogs have been prepared with the goal of preparing new peptidase inhibitors. Some of these amino acid syntheses are collected into this section. 

Design, synthesis and evaluation of azapeptides, oxapeptides and related heterocycles as inhibitors of D,D-peptidase and (3-lactamase 95F455. 

Another interesting target for this type of inhibitors is the dipeptidyl peptidase IV (DPP IV). This exodipeptidase, which can cleave peptides behind a proline residue is important in type 2 diabetes as it truncates the glucagon-like peptide 1. Taking into account the P2-Pi( Pro)-P,1 cleavage and the requirement for a free terminal amine, the synthesis of a suicide inhibitor was planned. It looked as if the the e-amino group of a P2 lysine residue could be cyclized because of the relative little importance of the nature of the P2 residue on the rate of enzymatic hydrolysis of known synthetic substrates. Therefore, anew series of cyclopeptides 11 was synthesized (Fig. 11.8). 

Ashton, W.T., Dong, H., Sisco, R.M., Doss, G.A., Leiting, B., Patel, R.A., Wu, J.K., Marsilio, F., Thornberry, N.A. and Weber, A.E. (2004) Diastereoselective synthesis and configuration-dependent activity of (3-substituted-cycloalkyl) glycine pyrrolidides and fhiazolidides as dipeptidyl peptidase IV inhibitors. Bioorganic at Medicinal Chemistry Letters, 14, 859-863. 

A. E. and Kim, D. (2007) Design, synthesis, and biological evaluation of triazolopiperazine-based P-amino amides as potent, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Bioorganic e[ Medicinal chemistry Letters, 17, 5934-5939. 

Bacterial cell wall synthesis inhibitor, d-ALANINE-d-ALANINE LIGASE BACTERIAL LEADER PEPTIDASE I Bacterial reorientation,... 

P. Van der Veken, I. Kertesz, K. Senten, A. Haemers, K. Augustyns, Synthesis of ( )- and (Z)-fluoro-olefin analogs of potent dipeptidyl peptidase IV inhibitors. Tetrahedron Lett. 44 (2003) 6231-6234. 

The hormone-hke peptide incretin stimulates the release of insuhn by a feedback process that involves cleaving the molecule to an inactive form. The protease enzyme dipeptidal peptidase (DPP) in turn cleaves incretin, in effect inactivating this enzyme. Inhibition of DPP consequently extends the action of incretin. This inhibition thus prevents the increased levels of blood glucose that mark diabetes. The protease inhibitor vidagliptin, which is modeled in part on the terminal sequence in DPP, has been found to sustain levels of insulin in Type II diabetics. The inhibition is apparently reversible in spite of the presence in the structure of the relatively reactive a-aminonitrile function. Construction of one intermediate in the convergent synthesis comprises the reaction of amino adamantamine (21-1) with a mixture of nitric and... 

Peterson olefination chemistry based upon tert-butyl fluoroacetate, generated in situ from the corresponding bromoester, has also been used in the synthesis of peptide isosteres [ 176,177]. Equation (58) shows the crucial early steps in the synthesis of an inhibitor of Dipeptidyl Peptidase IV. 

The ornithine related phosphonate (n = 3) can be guanidylated at the 4-amino group by treatment with formamidinesulfonic acid to provide Argp(OPh)2. This method can be used for the synthesis of substrate-related thrombin inhibitors such as Ac-Phe-Pro-Argp(OPh)2. 41 Proline analogues required a special approach and a few synthetic methods are reported since dipeptides of Prop(OPh)2 are excellent inhibitors of dipeptidyl peptidase IV (DPP IV or CD 26), the serine protease involved in immune response. 4 Diphenyl phosphite and dialkyl phosphites react smoothly with 1-pyrrolidine (3,4-dihydro-2//-pyrrole) trimer 20 to give the corresponding pyrrolidine-2-phosphonate 21 (Scheme 14). 42 ... 

Borloo, M., and I. De Meester. 1994. Dipeptidyl peptidase IV Development, design, synthesis and biological evaluation of inhibitors. Verh K Acad Geneeskd Belg 56 57. 

Senten K, Daniels L, Van der Veken P, De Meester 1, Lambeir 69. A-M, Scharpe S, Haemers A, Augustyns K. Rapid parallel synthesis of dipeptide diphenyl phosphonate esters as inhibitors of dipeptidyl peptidases. J. Comb. Chem. 2003 5 336-344. 70. 

Fukase, H., and Horii, S., Synthesis of valiolamine and its A-substituted derivatives AO-128, validox-ylamine G, and validamycin G via branched-chain inosose derivatives, J. Org. Chem., 57, 3651, 1992. Morgan, B.P., Holland, D.R., Matthews, B.W., and Bartlett, P.A., Structure-based design of an inhibitor of the zinc peptidase thermolysin, J. Am. Chem. Soc., 116, 3251, 1994. 

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