Treatment dipeptidyl peptidase-4 inhibitors

Case History JANUVIA (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes... 

Dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes... 

For recent reviews see Weber, A.E. (2004) Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. Journal of Medicinal Chemistry, 47, 4135-4141 (b)... 

Inhibitors of proline-specific dipeptidyl peptidases DPP-4 inhibitors as a novel approach for the treatment of type 2 diabetes. Expert Opinion on Therapeutic Patents, 15, 1387-1407 (d) von Geldern, T.W. and Trevillyan, J.M. 

C., Piteau, S., Demuth, H.-U., McIntosh, C.H.S. and Pederson, R. (2003) Dipeptidyl peptidase IV inhibitor treatment stimulates P-cell survival and islet neogenesis in streptozotodn-induced diabetic rats. Diabetes, 52, 741-750. 

A.E. (2006) (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-l-yl)-N,N-dimethyl-4-oxo-2-(4-[l,2,4]triazolo[l,5-a]pyridin-6-ylphenyl)butanamide a selective a-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Journal of Medicinal Chemistry, 49, 3614-3627. 

P.E. Wiedeman, J.M. Trevillyan, Dipeptidyl peptidase IV inhibitors for the treatment of impaired glucose tolerance and type 2 diabetes, Curr. Opin. Investig. Drugs (Thomson Curr. Drugs) 4 (2003) 412-420. 

K. Augustyns, P. Van der Veken, K. Senten, A. Haemers, Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of type 2 diabetes. Expert Opin. Ther. Patents 13 (2003) 499-510. 

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 ... 

Miller S, St Onge EL. Sitagliptin a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother 2006 40(7-8) 1336 l3. 

Although it is a candidate for the treatment of type 2 diabetes, it has to be injected subcutaneously and is extremely rapidly degraded by dipeptidyl peptidase IV. Analogues that are resistant to degradation and inhibitors of the degrading enzyme are being investigated. 

Merck have described 1,4-diazepine derivatives as potent dipeptidyl peptidase IV inhibitors for the treatment of diabetes with X studied extensively preclinically as a potential back-up compound to sitagliptan, marketed by Merck in 2006 as Januvia <2007BML49, 2007BML1903>. 

Some other peptides, e.g., dipeptidyl peptidase IV (8), endopeptidase 3.4.24.16 inhibitor (9), and a copolymer of tyrosine, glutamic acid, alanine, and lysine (10), have also demonstrated immunomodulatory activity. Thus analogues of these may some day play an important role in treatment of autoimmune and inflammatory diseases. It should also be noted that a vast number of naturally derived peptides also has demonstrated antimicrobial activity toward a wide range of pathogens (11), resulting in possible templates for further optimization studies clearly demonstrating the potential importance of peptides as pharmacological tools. 

The approval of sitagliptin (1) by the U.S. FDA in 2006 established dipeptidyl peptidase IV (DPP-4) inhibitors as an important new therapy for the treatment of type 2 diabetes.4 7 DPP-4 inhibitors stimulate insulin secretion indirectly by enhancing the action of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (G1P). GLP-1 and G1P stimulate insulin secretion in a... 

Sinclair, E. M., and Drucker, D. J. 2005. Glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase IV inhibitors new therapeutic agents for the treatment of type 2 diabetes. Curr. Opin. Endocrinol. Diabet., 12,146-151. 

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