Dataset Information

ZY15557, a novel, long acting inhibitor of dipeptidyl peptidase-4, for the treatment of Type 2 diabetes mellitus.

ABSTRACT:

Background and purpose

Dipeptidyl peptidase (DPP)-4 inhibitors increase levels of glucagon-like peptide-1 (GLP-1) and provide clinical benefit in the treatment of type 2 diabetes mellitus. As longer acting inhibitors have therapeutic advantages, we developed a novel DPP-4 inhibitor, ZY15557, that has a sustained action and long half-life.

Experimental approach

We studied the potency, selectivity, efficacy and duration of action of ZY15557, in vitro, with assays of DPP-4 activity. In vivo, the pharmacodymamics and pharmacokinetics of ZY15557 were studied, using db/db mice and Zucker fatty rats, along with normal mice, rats, dogs and non-human primates.

Key results

ZY15557 is a potent, competitive and long acting inhibitor of DPP-4 (K_i 5.53 nM; K_off 3.2 × 10^-4 ·s^-1 , half-life 35.8 min). ZY15557 treatment inhibited DPP-4 activity, and enhanced active GLP-1 and insulin in mice and rats, providing dose-dependent anti-hyperglycaemic effects. Anti-hyperglycaemic effects were also observed in db/db mice and Zucker fatty rats. Following oral dosing, ZY15557 significantly inhibited plasma DPP-4 activity, determined ex vivo, in mice and rats for more than 48 h, and for up to 168 h in dogs and non-human primates. Allometric scaling predicts a half-life for ZY15557 in humans of up to 60 h.

Conclusions and implications

ZY15557 is a potent, competitive and long acting DPP-4 inhibitor. ZY15557 showed similar DPP-4 inhibition across different species. ZY15557 showed excellent oral bioavailability in preclinical species. It showed a low plasma clearance (CL) and large volume of distribution (V_ss ) across species, resulting in an extended half-life.

SUBMITTER: Jain MR

PROVIDER: S-EPMC5481660 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

ZY15557, a novel, long acting inhibitor of dipeptidyl peptidase-4, for the treatment of Type 2 diabetes mellitus.

Jain Mukul R MR Joharapurkar Amit A AA Kshirsagar Samadhan G SG Patel Vishal J VJ Bahekar Rajesh H RH Patel Harilal V HV Jadav Pradip A PA Patel Pankaj R PR Desai Ranjit C RC

British journal of pharmacology 20170613 14

<h4>Background and purpose</h4>Dipeptidyl peptidase (DPP)-4 inhibitors increase levels of glucagon-like peptide-1 (GLP-1) and provide clinical benefit in the treatment of type 2 diabetes mellitus. As longer acting inhibitors have therapeutic advantages, we developed a novel DPP-4 inhibitor, ZY15557, that has a sustained action and long half-life.<h4>Experimental approach</h4>We studied the potency, selectivity, efficacy and duration of action of ZY15557, in vitro, with assays of DPP-4 activity. ...[more]

PMID: 28452143

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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:IntroductionThe use of antihyperglycemic agents (AHA), especially insulin and sulfonylureas (SU), is a risk factor for hypoglycemia. Despite the significant clinical and economic burdens associated with hypoglycemia and the decreasing use of SU in favor of other oral AHA, relatively little is known about hypoglycemia trends specific to the use of non-insulin AHA. We sought to estimate annual hypoglycemia event rates and costs among patients with type 2 diabetes mellitus (T2DM) who started either SU or dipeptidyl peptidase-4 inhibitors (DPP-4i) and to predict rates and costs in the absence of DPP-4i.MethodsTruven's MarketScan Commercial Claims database was used to estimate hypoglycemia event rates and costs from 2007 to 2013. Hypoglycemia, defined using diagnosis codes, was assessed during the 12 months following SU (n = 245,201) or DPP-4i (n = 176,786) initiation by adults with T2DM. Coefficients from a Poisson regression model used to estimate the impact of patient characteristics on hypoglycemia rates for patients who started SU were used to predict rates for patients who started DPP-4i had they started SU instead.ResultsHypoglycemia events per 100 patient-years (costs per event) ranged from 5.4 ($565) in 2007 to 10.4 ($1154) in 2013 for patients starting SU; rates (costs) for patients starting DPP-4i ranged from 3.2 ($308) in 2007 to 6.4 ($482) in 2013. Predicted hypoglycemia rates would have been 5.3-9.9 per 100 person-years for patients who started DPP-4i had they started SU instead. Starting DPP-4i, rather than SU, would have resulted in national savings of $750.3 million in healthcare costs due to avoided hypoglycemia events during this period.ConclusionsHypoglycemia rates and costs were consistently higher for patients who started SU rather than DPP-4i. The overall burden of hypoglycemia could be lowered substantially in the USA if, when feasible, patients with T2DM initiate DPP-4i instead of SU.FundingMerck & Co., Inc., Kenilworth, NJ USA.

Dataset Information

ZY15557, a novel, long acting inhibitor of dipeptidyl peptidase-4, for the treatment of Type 2 diabetes mellitus.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

ZY15557, a novel, long acting inhibitor of dipeptidyl peptidase-4, for the treatment of Type 2 diabetes mellitus.

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