Dipeptidyl peptidase IV

The incretin effect is reduced in type 2 diabetes, and this is attributed, at least in part, to reduced secretion of GLP-1. The biological actions of GLP-1 remain essentially intact in type 2 diabetes, but administration of extra GLP-1 is not a practical therapeutic option because the peptide is degraded rapidly if A < 2 min) by the enzyme dipeptidyl peptidase IV (DPP-4). DPP-4 cleaves the N-terminal dipeptide from many of the peptides that have either an alanine or a proline residue penultimate to the N-terminus (Fig. 6). 

DPP-1V inhibitors Inhibition of the dipeptidyl peptidase IV (by sitagliptin or vildagliptin) prolongs the duration of action of endogenous GLP-1 and thereby... 

Importantly, both incretins when secreted by the intestine are rapidly degraded by the dipeptidyl peptidase IV (DPPFV), which removed the two amino-terminus histidine-alanine residues, thereby, inactivating the incretins. This enzyme is present at the surface of the epithelial intestinal cells and capillaries in the vicinity of the K and L cells secreting GIP and GLP-1, respectively. It is also present in the... 

An efficient biocatalytic method for the production of amides in multigrara scale has been developed for the synthesis of a pyrrole-amide, which is an intermediate for the synthesis of the dipeptidyl peptidase IV that regulates plasma levels of the insulinotropic proglucagon. CALB catalyzes the ammonolysis of the ester with ammonium carbamate as source of ammonia (Scheme 7.8) [22]. The use of ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol by-products. 

McAlexander L, Sinha T, et al Dipeptidyl peptidase IV deficiency increases susceptibifity to angiotensinconverting enzyme inhibitor-induced peritracheal edema. J Allergy Chn Immunol 2007 120 403-408. 

Hosono O, HommaT, Kobayashi H et al (1999) Decreased dipeptidyl peptidase IV enzyme activity of plasma soluble CD26 and its inverse correlation with HIV-1 RNA in HIV-1 infected individuals. Qin Immunol 91 283-295... 

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). 

Nguyen, C. Blanco, J. Mazaleyrat, J.-P. Krust, B. Callebaut, C. Jacotot, E. Hovanessian, A. G. Wakselman, M. Specific and irreversible cyclopeptide inhibitor of dipeptidyl peptidase IV activity of the T-cell activation antigen CD26. J. Med. Chem. 1998, 41, 2100-2110. 

Lambeir AM, Proost P, Durinx C, et al. Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family. J Biol Chem 2001 276(32) 29839-29845. 

Ludwig A, Schiemann F, Mentlein R, et al. Dipeptidyl peptidase IV (CD26) on T cells cleaves the CXC chemokine CXCL11 (I-TAC) and abolishes the stimulating but not the desensitizing potential of the chemokine. J Leukoc Biol 2002 72 183-191. 

Struyf S, Proost P, Schols D, et al. CD26/dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3. J Immunol 1999 162 4903 1909. 

If a patient has inadequate control on two drugs, adding a third class can be considered (e.g., a glitazone, exenatide, a dipeptidyl peptidase-IV inhibitor, or basal insulin). Therapy should be guided by the A 1C, FPG, cost, additional benefits (e.g., weight loss), and avoidance of side effects). 

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

A virtual screen of 10,000 primary amine fragments against dipeptidyl peptidase IV (a diabetes target) identified a number of hits, as determined by bioassay screening at 100 pM, e.g. 6 [21]. An X-ray structure of this fragment confirmed the predicted binding mode in the Si pocket and inspired a structure-based hypothesis that eventually led to identification of a potent series of DPP-IV inhibitors [22],... 

R. P. Pauly, F. Rosche, M. Wermann, C. H. McIntosh, R. A. Pederson, and H. U. Demuth. Investigation of Glucose-Dependent Insulinotropic Polypeptide-(l-42) and Glucagon-like Peptide-1-(7-36) Degradation In Vitro by Dipeptidyl Peptidase IV Using Matrix-Assisted... 

A similar but simpler 4-imino-hexahydropyrrolo[l,2-tf]pyrazin-l(277)-one 311 was prepared starting from the product obtained by nucleophilic substitution of a primary amine to the bromoacetamide of the L-prolylnitrile 310 (Scheme 40). The cyclization occurred directly in basic medium by refluxing for 96 h in EtOAc. This compound showed a potent activity as an orally bioavailable dipeptidyl peptidase IV inhibitor with anti-hyperglycemic properties <2003JME2774>. 

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

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