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Anti-Diabetic Drugs
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
Another ‘incretin’-based therapy includes the DPP-4 inhibitors or the ‘gliptin’ class of drugs, which are oral anti-diabetic medications. DPP-4 is an enzyme present as a transmembrane protein that acts upon the endogenous incretins such as GLP-1 and degrades them. It is due to this enzyme that the half-life of endogenous GLP-1 is almost 5 minutes, which is pharmacologically much less. Thus, inhibition of DPP-4 results in the natural action of endogenous GLP-1 which enhances the insulin secretion. Sitagliptin (Januvia; Merck) was the first drug in this class to be approved by the US FDA in 2006, followed by vildagliptin (Galvus; Novartis) in 2007 [1,15]. Other DPP-4 inhibitors are saxagliptin (Onglyza; AstraZeneca), alogliptin (Nesina; Takeda Pharmaceuticals), linagliptin (Tradjenta; Eli Lilly), trelagliptin (Zafatek; Takeda Pharmaceuticals) and teneligliptin (Tenelia; Daiichi Sankyo). The dosage regimens of these DPP-4 inhibitors are as follows: Sitagliptin (25/50/100 mg once daily), saxagliptin (2.5/5 mg once daily), vildagliptin (50/100 mg per day, not exceeding 100 mg daily), alogliptin (25 mg once daily), linagliptin (5 mg once daily), trelagliptin (100 mg once weekly) and teneligliptin (20 mg once daily). These DPP-4 inhibitors have been used as monotherapy or in combination with metformin, sulphonylureas, TZDs and insulin [16–23]. According to various studies and reports, the major adverse effects associated with DPP-4 inhibitors are pancreatitis, renal problems and even heart failure, which have also been put on the FDA warning list [24]. Therefore, these drugs should be used very cautiously in patients.
Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
As can be seen in Fig. 11.27, three gliptins, alogliptin 44, linagiptin 45 and trelagliptin 50 shared a common moiety, (R)-piperidin-3-amine (R)-66, in their chemical structures, which apropos is the only chiral center present in both drugs. Therefore, this enantiopure amine is required in the chemical synthesis of 44 (Feng et al., 2007a; Feng et al., 2007b; Ludescher et al., 2010), 45 (Eckhardt et al., 2007) and 50 (Zhang et al., 2011b) Although there are different chemical methods to produce this homochiral (R)-66, the use of transaminases allows very clean methodologies. Thus, Hoehne et al (Hoehne et al., 2008) described the kinetic resolution of racemic N-protected 3-aminopiperidine 64, as shown in Fig. 11.27. Enzymatic transaminase-catalyzed kinetic resolution of 64 to produce enantiopure R-65.
Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial
Published in Current Medical Research and Opinion, 2019
Shu Meguro, Shingo Matsui, Hiroshi Itoh
Trelagliptin is the first once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor, which controls glucose levels by inhibiting DPP-47,8. DPP-4 breaks down glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which have important roles in glucose homeostasis9. The inhibition of DPP-4 prolongs the activity of endogenous GLP-1 and GIP, thereby improving glycemic control10. Phase 3 findings in patients with type 2 diabetes mellitus demonstrated that less frequent dosing with trelagliptin was non-inferior in reducing hemoglobin A1c (HbA1c) to the once-daily DPP-4 inhibitor, alogliptin, and had a comparable efficacy and safety profile11. These results were further supported by a long-term phase 3 study of trelagliptin, as monotherapy or in combination with an existing oral antidiabetic drug, which demonstrated favorable safety and efficacy over 52 weeks12.
An up-to-date evaluation of alogliptin benzoate for the treatment of type 2 diabetes
Published in Expert Opinion on Pharmacotherapy, 2019
Jingbo Hu, Chunlin Yang, Hongbo Wang, Jing Li, Xueying Tan, Jinhui Wang, Bin Zhang, Yufen Zhao
The better glycemic control was observed in subjects treated with alogliptin benzoate 25 mg once daily in a randomized, double-blind, phase III study (ClinicalTrials.gov Identifier: NCT01632007) at 26 sites in Japan [27]. In this study, 243 enrolled subjects were randomly treated with trelagliptin, alogliptin benzoate or placebo. It was found that the least squares (LS) mean changes (s.e.) in HbA1c was −0.33% in subjects with trelagliptin (SE 0.059) and −0.45% in those with alogliptin benzoate (0.061) based on the ANCOVA model, and the least squares mean difference (trelagliptin minus alogliptin benzoate) of change from baseline in HbA1c was 0.11% (95% confidence interval [CI] −0.054 to 0.281), suggesting the similar anti-diabetic activity between alogliptin benzoate and trelagliptin [27]. The significant changes of HbA1c in both alogliptin benzoate and trelagliptin groups were observed in comparison to placebo. In addition, frequencies of adverse event were similar between alogliptin benzoate and trelagliptin, and both were well tolerated [27].
Advances in computer-aided drug design for type 2 diabetes
Published in Expert Opinion on Drug Discovery, 2022
Wanqiu Huang, Luyong Zhang, Zheng Li
The weekly doses of trelagliptin and omarigliptin [75] have been approved by Japan, but the high incidence of serious adverse events limited clinical application. Hence, Li et al. [76] attempted to identify a novel and safe DPP-IV inhibitor with long-acting antidiabetic effects. The authors identified a new DPP-IV inhibitor compound 16 based on a previous study (Figure 4A); however, the long-acting effect of this compound was still undesirable. The receptor–ligand interaction suggested that Arg358 formed a closed conformation with compound 16, which might be at crucial factor in the slow binding kinetics profile of compound 16. To optimize the ligand-protein binding kinetics and pharmacokinetic profile of compound 16, Arg358 was locked in a closed conformation during subsequent structural optimization. Three analogs of compound 16 were calculated using fragment molecular orbital (FMO) and quantum-mechanical (QM) methods, which determined that the methoxy group was suitable for replacement. After the energy analysis, a linear 2.4 Å cyan group was introduced in the R2 position. Hence, the superior compound 17 was obtained, which could maintain Arg358 in a closed conformation. The surface plasmon resonance assay indicated that compound 17, with DPP-IV protein, had a faster binding rate and slower dissociation rate than compound 16 and sitagliptin. Pharmacokinetic studies in mice showed that compound 17 had a large exposure, wide distribution, slow clearance rate, and long half-life. This case study indicated that the FMO-QM method could be a useful tool to guide the structural optimization of some key residues in ligand-protein complexes.