Design and synthesis of long-acting inhibitors of dipeptidyl peptidase IV

Kondo, Takashi; Sugimoto, Isamu; Nekado, Takahiro; Ochi, Kenya; Ohtani, Tazumi; Tajima, Yuko; Yamamoto, Sachiko; Kawabata, Kazuhito; Nakai, Hisao; Toda, Masaaki

doi:10.1016/j.bmc.2007.01.033

Cited by 19 publications

(6 citation statements)

References 47 publications

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“…Like saxagliptin and vildagliptin, anagliptin is a cyanopyrrolidine derivative possessing a prolylprolinenitrile scaffold [ 113 , 121 ], available for clinical use in Japan since 2012. Since this compound is not generally used in countries other than Japan, there is a paucity of reports investigating its effects.…”

Section: Reviewmentioning

confidence: 99%

Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes

Fisman

Tenenbaum

2015

Cardiovasc Diabetol

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The traditional oral pharmacological therapy for type 2 diabetes mellitus (T2DM) has been based on the prescription of metformin, a biguanide, as first line antihyperglycemic agent world over. It has been demonstrated that after 3 years of treatment, approximately 50 % of diabetic patients could achieve acceptable glucose levels with monotherapy; but by 9 years this had declined to only 25 %. Therefore, the implementation of a combined pharmacological therapy acting via different pathways becomes necessary, and its combination with a compound of the sulfonylurea group was along decades the most frequently employed prescription in routine clinical practice. Meglitinides, glitazones and alpha-glucosidase inhibitors were subsequently developed, but the five mentioned groups of oral antihyperglycemic agents are associated with variable degrees of undesirable or even severe cardiovascular events. The gliptins—also called dipeptidyl peptidase 4 (DPP4) inhibitors—are an additional group of antidiabetic compounds with increasing clinical use. We review the status of the gliptins with emphasis on their capabilities to positively or negatively affect the cardiovascular system, and their potential involvement in major adverse cardiovascular events (MACE). Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin are the compounds currently in clinical use. Regardless differences in chemical structure and metabolic pathways, gliptins as a group exert favorable changes in experimental models. These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis. In addition, increased adiponectin levels and modest decreases in lipidemia and blood pressure were reported. In clinical settings, several trials—notably the longer one, employing sitagliptin, with a mean follow-up period of 3 years—did not show an increased risk for ischemic events. Anyway, it should be emphasized that the encouraging results from basic science were not yet translated into clinical evidence, probably due the multiple and pleiotropic enzymatic effects of DPP4 inhibition. Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased. Gliptins as a group constitute a widely accepted therapy for the management of T2DM, usually as a second-line medication. Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven.

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Section: Reviewmentioning

confidence: 99%

Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes

Fisman

Tenenbaum

2015

Cardiovasc Diabetol

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“…The aryl substitution on the C-4 position of the pyrrolidine ring has been noted to improve the stability and duration of DPP4 inhibitors. 40 In addition, the fluorine substituent on the C-4 position of the pyrrolidine ring has been reported to provide good inhibitory properties, selectivity, and pharmacokinetic profiles. 41 The preferable pharmacokinetic profile may result from a lipophilic property governed by a planar aromatic ring and halogen atoms, which facilitates cell entry to the target site of action.…”

Section: Resultsmentioning

confidence: 99%

Navigating the chemical space of dipeptidyl peptidase-4 inhibitors

Shoombuatong¹,

Prachayasittikul²,

Anuwongcharoen³

et al. 2015

DDDT

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This study represents the first large-scale study on the chemical space of inhibitors of dipeptidyl peptidase-4 (DPP4), which is a potential therapeutic protein target for the treatment of diabetes mellitus. Herein, a large set of 2,937 compounds evaluated for their ability to inhibit DPP4 was compiled from the literature. Molecular descriptors were generated from the geometrically optimized low-energy conformers of these compounds at the semiempirical AM1 level. The origins of DPP4 inhibitory activity were elucidated from computed molecular descriptors that accounted for the unique physicochemical properties inherently present in the active and inactive sets of compounds as defined by their respective half maximal inhibitory concentration values of less than 1 μM and greater than 10 μM, respectively. Decision tree analysis revealed the importance of molecular weight, total energy of a molecule, topological polar surface area, lowest unoccupied molecular orbital, and number of hydrogen-bond donors, which correspond to molecular size, energy, surface polarity, electron acceptors, and hydrogen bond donors, respectively. The prediction model was subjected to rigorous independent testing via three external sets. Scaffold and chemical fragment analysis was also performed on these active and inactive sets of compounds to shed light on the distinguishing features of the functional moieties. Docking of representative active DPP4 inhibitors was also performed to unravel key interacting residues. The results of this study are anticipated to be useful in guiding the rational design of novel and robust DPP4 inhibitors for the treatment of diabetes.

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“…是一类丝氨酸蛋白酶 [1] ，能快速地降解胰高血糖素样肽 1(GLP-1，glucagon-like peptide-1)。而 GLP-1 能够促进胰岛素的合成和分泌，降低餐后血糖 [2] 。抑制 DPP-Ⅳ能增强内源性 GLP-l 的作用，从而提高血液中胰岛素的水平，降低糖尿病人的血糖水平 [3] 。因此 DPP-Ⅳ抑制剂被认为是一种新型的抗糖尿病治疗药物 [4] 。2006 年默克公司的抗糖尿病治疗药物西他列汀…”

Section: Dpp-ⅳ抑制剂三维药效团模型构建 *unclassified

3D Pharmacophore Model Construction of DPP-Ⅳ Inhibitors

韩天佼¹,

李悦青²,

谷俊峰³

et al. 2012

HJCET

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The 3D pharmacophore model of DPP-Ⅳ inhibitors was established using the Discovery Studio software with the training set of 20 DPP-Ⅳ inhibitors. The best pharmacophore hypothesis (Hypo 1) consists of one hydrogen-bond acceptor, one hydrophobic point, one positive ionizable group, one aromatic ring as well as five excluded volumes. Fischer's validation clearly shows that proposed Hypo 1 has highly predictive ability and can be efficiently used as a 3D query for virtual screening to retrieve potential inhibitors from ZINC databases. The hit compounds subsequently were docked into the DPP-Ⅳ active site and 21 compounds were obtained based on PLP2 scoring function. Therefore, this study could provide scientific basis for denovo design of DPP-Ⅳ inhibitors.

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Design and synthesis of long-acting inhibitors of dipeptidyl peptidase IV

Cited by 19 publications

References 47 publications

Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes

Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes

Navigating the chemical space of dipeptidyl peptidase-4 inhibitors

3D Pharmacophore Model Construction of DPP-Ⅳ Inhibitors

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