K579, a slow-binding inhibitor of dipeptidyl peptidase IV, is a long-acting hypoglycemic agent

Takasaki, Kotaro; Iwase, Miho; Nakajima, Takao; Ueno, Kimihisa; Nomoto, Yuji; Nakanishi, Satoshi; Higo, Katsuya

doi:10.1016/j.ejphar.2003.12.029

Cited by 32 publications

(16 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we investigated the antihyperglycemic effects of vildagliptin in streptozotocin induced diabetic rats, which exhibited a mild decline in glucose tolerance due to loss of earlyphase insulin secretion (Takasaki et al, 2004). These diabetic rats experienced an approximately 70% decrease in pancreatic insulin content.…”

Section: Dpp-4 Inhibitors Augment the Effects Of Incretin Hormones Bymentioning

confidence: 99%

Vildagliptin selectively ameliorates GLP-1, GLUT4, SREBP-1c mRNA levels and stimulates β-Cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes

Akarte

Srinivasan

Gandhi

2012

Journal of Diabetes and its Complications

View full text Add to dashboard Cite

Section: Dpp-4 Inhibitors Augment the Effects Of Incretin Hormones Bymentioning

confidence: 99%

Vildagliptin selectively ameliorates GLP-1, GLUT4, SREBP-1c mRNA levels and stimulates β-Cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes

Akarte

Srinivasan

Gandhi

2012

Journal of Diabetes and its Complications

View full text Add to dashboard Cite

“…The differences in the position of peripheral residues is the source of the diverse specificities exhibited by these proteases. Figure 2 shows the inhibition of PI-PLC using two gliptins - vildagliptin (LAF-237) 23 and K579 24 . PI-PLC catalyzes hydrolysis of phospholipids to yield diacylglycerol and a phosphoryl alcohol.…”

Section: Resultsmentioning

confidence: 99%

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

Chakraborty¹,

Rendón-Ramírez²,

Ásgeirsson³

et al. 2015

F1000Res

View full text Add to dashboard Cite

The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

show abstract

“…Nevertheless, K579 had an apparent longer duration of action than NVP-DPP728 in vivo, as judged by the inhibition of plasma DPP-IV, and the glucose excursion after a second glucose challenge at 4.5h. It was then shown, that an active oxide metabolite of K579 undergoes enterohepatic circulation and is probably responsible for the sustained duration of action (possibly together with slow dissociation of the enzymeinhibitor complex, and improved chemical stability) [146][147][148]. Interestingly, active oxide metabolites also played a role in the discoveries of vildagliptin and saxagliptin.…”

Section: Chemical Stabilitymentioning

confidence: 98%

11 Years of Cyanopyrrolidines as DPP-IV Inhibitors

Peters

2007

CTMC

View full text Add to dashboard Cite

Cyanopyrrolidines (cyanopyrrolidides, pyrrolidine-2-nitriles, prolinenitriles) as inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV, DP IV, CD26, EC 3.4.14.5) were first reported in 1995. The interest in this compound class grew immensely when DPP-IV was discovered as a target for the treatment of type 2 diabetes. The research on cyanopyrrolidines cumulated in the discoveries of vildagliptin (LAF237, NVP-LAF237) and saxagliptin (BMS-477118). These compounds entered Phase III clinical trials in 2004 and 2005, respectively, and an application for market approval has been filed for vildagliptin in 2006. Today cyanopyrrolidines are, as judged by the numbers of patent applications, the most prominent of several series of DPP-IV inhibitors, and have the potential to become valuable medicines for type 2 diabetes in the near future. This review summarizes some historical aspects of the discovery of cyanopyrrolidine DPP-IV inhibitors, and then focuses mainly on structure-activity-relationships, the evolution of different subseries, the possibilities to improve on the chemical instability that is associated with this compound class, and on the discoveries of vildagliptin and saxagliptin. Within this context, the properties of individual compounds and results from biological studies are discussed. The rationale of DPP-IV inhibition, clinical data, and the relevance of selectivity over related proteases are extensively reviewed in other contributions to this issue of Curr. Top. Med. Chem., and are therefore only very briefly touched.

show abstract

K579, a slow-binding inhibitor of dipeptidyl peptidase IV, is a long-acting hypoglycemic agent

Cited by 32 publications

References 34 publications

Vildagliptin selectively ameliorates GLP-1, GLUT4, SREBP-1c mRNA levels and stimulates β-Cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes

Vildagliptin selectively ameliorates GLP-1, GLUT4, SREBP-1c mRNA levels and stimulates β-Cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

11 Years of Cyanopyrrolidines as DPP-IV Inhibitors

Contact Info

Product

Resources

About