(2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:  A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

Kim, Dooseop; Wang, Liping; Beconi, Maria; Eiermann, George J.; Fisher, Michael H.; He, Huaibing; Hickey, Gerard J.; Kowalchick, Jennifer E.; Leiting, Barbara; Lyons, Kathryn A.; Marsilio, Frank; McCann, Margaret E.; Patel, Reshma A.; Petrov, A. N.; Scapin, Giovanna; Patel, Sangita; Roy, Ranabir Sinha; Wu, Joseph K.; Wyvratt, Matthew J.; Zhang, Bei B.; Zhu, Lan; Thornberry, Nancy A.; Weber, Ann E.

doi:10.1021/jm0493156

Cited by 792 publications

(513 citation statements)

References 37 publications

Supporting

Mentioning

493

Contrasting

Unclassified

Order By: Relevance

“…In an animal experiment, LC15-0444 shows inhibition of DPPIV activity by Z80%, which is associated with a maximal short-term lowering of glucose levels. 22 In addition, a twofold augmentation of postprandial active GLP-1 levels is associated with similar effects. 22 A phase I study conducted in healthy Korean male subjects after single administration of LC15-0444 at doses of either 25, 50, 100, 200, 400, or 600 mg found that a single dose of LC15-0444 exhibited linear PK properties over the range of 50-400 mg in study subjects.…”

Section: Discussionmentioning

confidence: 97%

“…22 In addition, a twofold augmentation of postprandial active GLP-1 levels is associated with similar effects. 22 A phase I study conducted in healthy Korean male subjects after single administration of LC15-0444 at doses of either 25, 50, 100, 200, 400, or 600 mg found that a single dose of LC15-0444 exhibited linear PK properties over the range of 50-400 mg in study subjects. 23 In addition, PK characteristics were not significantly influenced by food, and doses Z200 mg of LC15-0444 inhibited plasma DPP IV activity by 480% over a 24-h dosing interval, and a 600 mg dose increased active GLP-1 levels after a standardized meal.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFb1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-kB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…,5-trifluorophenyl)butan-2-amine is a powerful, vocally active (DPP-IV) inhibitor with excellent selectivity above the other prolineselective peptidases [16].…”

Section: β-Amino Amidesmentioning

confidence: 99%

?-Amino Acids: Role in Human Biology and Medicinal Chemistry - A Review

Riaz¹,

Fazal-ur-Rehman²,

Ahmad³

2017

Med chem

View full text Add to dashboard Cite

Abstractβ-amino acids are an important class of macromolecules. They play role in life for survival. β-amino acids gained significant interest due to their interesting pharmaceutical uses as hypoglycemic, antiketogenic characteristics, sterile and antifungal activities, anthelminthic as well as potent insecticidal characteristics. These are vital building blocks for the preparation of pharmaceutical and agrochemical target molecules. These are utilized in development of drugs, bimolecular structure and molecular recognition. They are also important in treatment of different diseases which are viral to human health. They play important role in regulation of nutritional metabolism and immunity. It has also led to their wider adoption as intermediates in new drugs and has been a focus of considerable attention in medicinal chemistry. β-amino acids have found extensive applications as components of biologically active peptides and small molecule pharmaceuticals. Synthetic derivatives of biologically relevant peptides incorporating β-amino acids often display interesting pharmacological activity, with increased potency and enzymatic stability. β-peptides participate in arrangement of incredible stable auxiliary structures. This review summarizes recent developments about the different roles of β-amino acids in human biology and some implications in medicinal chemistry.

show abstract

“…1 The incretin hormone glucagon-like peptide 1 (GLP-1) has been the subject of intense research efforts related to the treatment of type 2 diabetes. 2 Secreted from the L cells of the small intestine, 3 GLP-1 stimulates glucose-induced insulin secretion, inhibits glucagon secretion, 4 and delays the gastric emptying, all of which are beneficial in controlling the blood glucose. 5 GLP-1 is one of the substrates of dipeptidyl peptidase-4 (DPP-4, also known as CD26).…”

mentioning

confidence: 99%

Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors

Jiang

Zhou

Chen

et al. 2015

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

Dipeptidyl peptidase-4 (DPP-4) inhibitors are accepted as a favorable class of agents for the treatment of type 2 diabetes. Herein, a series of fused β-homophenylalanine derivatives as novel DPP-4 inhibitors were designed, synthesized, and evaluated for their inhibitory activities against DPP-4. Most of them displayed excellent DPP-4 inhibitory activities and good selectivity. Among them, 9aa, 18a, and 18m also showed good efficacy in an oral glucose tolerance test (OGTT) in ICR mice. Moreover, when dosed 8 h prior to glucose challenge, 18m showed significantly greater potency than sitagliptin. It thus provides potential candidates for the further development into potent drugs targeting DPP-4.

show abstract

(2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

Cited by 792 publications

References 37 publications

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

?-Amino Acids: Role in Human Biology and Medicinal Chemistry - A Review

Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors

Contact Info

Product

Resources

About