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Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4).

ABSTRACT: Compounds that contain (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid substituted with bicyclic amino moiety (2-aza-bicyclo[2.2.1]heptane) were designed using molecular modelling methods, synthesised, and found to be potent DPP-4 (dipeptidyl peptidase-4) inhibitors. Compound 12a (IC50 = 16.8 ± 2.2 nM), named neogliptin, is a more potent DPP-4 inhibitor than vildagliptin and sitagliptin. Neogliptin interacts with key DPP-4 residues in the active site and has pharmacophore parameters similar to vildagliptin and sitagliptin. It was found to have a low cardiotoxic effect compared to sitagliptin, and it is superior to vildagliptin in terms of ADME properties. Moreover, compound 12a is stable in aqueous solutions due to its low intramolecular cyclisation potential. These findings suggest that compound 12a has unique properties and can act as a template for further type 2 diabetes mellitus drug development.

SUBMITTER: Maslov IO

PROVIDER: S-EPMC8949241 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4).

Maslov Ivan O IO Zinevich Tatiana V TV Kirichenko Olga G OG Trukhan Mikhail V MV Shorshnev Sergey V SV Tuaeva Natalya O NO Gureev Maxim A MA Dahlén Amelia D AD Porozov Yuri B YB Schiöth Helgi B HB Trukhan Vladimir M VM

Pharmaceuticals (Basel, Switzerland) 20220222 3

Compounds that contain (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid substituted with bicyclic amino moiety (2-aza-bicyclo[2.2.1]heptane) were designed using molecular modelling methods, synthesised, and found to be potent DPP-4 (dipeptidyl peptidase-4) inhibitors. Compound <b>12a</b> (IC50 = 16.8 ± 2.2 nM), named neogliptin, is a more potent DPP-4 inhibitor than vildagliptin and sitagliptin. Neogliptin interacts with key DPP-4 residues in the active site and has pharmacophore parameters si ...[more]

PMID: 35337071

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Project description:Dipeptidyl peptidase IV inhibitor (DPP-4i) has been shown to act either as a promoter or as a suppressor for cancer. Although epidemiologic studies suggest that DPP-4i does not correlate with the development of malignancies, its effects on cancer metastases are controversial. We evaluated the impact of DPP-4i on postoperative outcomes of the diabetic patients with colorectal cancer and microscopic features of the resected tumors. In 260 consecutive patients with type 2 diabetes mellitus (T2DM) who underwent curative resection of colorectal cancer, the correlation between DPP-4i use and prognosis was retrospectively examined. Expression of Zeb1 on tumor cells and density of infiltrating immune cells were quantitatively evaluated with multicolor IHC in 40 tumors from DPP-4i users, 40 tumors from propensity score-matched users, and 40 tumors from nonusers. Postoperative disease-free survival (DFS) was significantly lower in 135 patients treated with DPP-4i compared with 125 nontreated patients [5-year DFS, 73.7% vs. 87.4%; HR, 1.98; 95% confidence interval (CI), 1.05-3.71; P = 0.035]. IHC revealed that the number of Zeb1+ tumor cells increased in tumors from DPP-4i-treated patients than tumors from nonusers (P < 0.01). The densities of CD3+ and CD8+ T cells were significantly lower in tumors from DPP-4i users (P < 0.01) with decreased density of tertiary lymphoid structures (P < 0.001). However, the density of M2-type tumor-associated macrophages with CD68+ CD163+ phenotypes was significantly higher (P < 0.01) in tumors from DPP-4i users. Exposure of colorectal cancer to DPP-4i may accelerate epithelial-to-mesenchymal transition (EMT) creating a tumor-permissive immune microenvironment, which might impair the outcomes of the patients with colorectal cancer and T2DM.SignificanceDPP-4i has been shown to enhance the antitumor effects of immunotherapy. However, we found that DPP-4i significantly impairs the outcomes of patients with colorectal cancer who underwent curative resection, possibly through acceleration of EMT and creation of a tumor-permissive immune microenvironment. This suggests that DPP-4i must be used with caution until its safety is fully confirmed by further studies of the mechanistic effects on existing cancers in humans.

Project description:Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular permeability and cause tissue edema in animals. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor-associated angioedema. This case-control study tested the hypothesis that dipeptidyl peptidase IV activity and antigen are decreased in sera of patients with a history of angiotensin-converting enzyme inhibitor-associated angioedema. Fifty subjects with a history of angiotensin-converting enzyme inhibitor-associated angioedema and 176 angiotensin-converting enzyme inhibitor-exposed control subjects were ascertained. Sera were assayed for angiotensin-converting enzyme activity, aminopeptidase P activity, aminopeptidase N activity, dipeptidyl peptidase IV activity, and antigen and the ex vivo degradation half-lives of bradykinin, des-Arg(9)-bradykinin, and substance P in a subset. The prevalence of smoking was increased and of diabetes decreased in case versus control subjects. Overall, dipeptidyl peptidase IV activity (26.6+/-7.8 versus 29.6+/-7.3 nmol/mL per minute; P=0.026) and antigen (465.8+/-260.8 versus 563.1+/-208.6 ng/mL; P=0.017) were decreased in sera from individuals with angiotensin-converting enzyme inhibitor-associated angioedema compared with angiotensin-converting enzyme inhibitor-exposed control subjects without angioedema. Dipeptidyl peptidase IV activity (21.5+/-4.9 versus 29.8+/-6.7 nmol/mL per minute; P=0.001) and antigen (354.4+/-124.7 versus 559.8+/-163.2 ng/mL; P=0.003) were decreased in sera from cases collected during angiotensin-converting enzyme inhibition but not in the absence of angiotensin-converting enzyme inhibition. The degradation half-life of substance P correlated inversely with dipeptidyl peptidase IV antigen during angiotensin-converting enzyme inhibition. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema.

Dataset Information

Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4).

Publications

Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4).

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