含4-甲基噻唑环的新型二肽基肽酶IV抑制剂的设计、合成及降血糖活性测试

目的：合成一类新型的以4-噻唑环为母体的二肽基肽酶IV (DPP-IV)抑制剂,测试并研究它们的降血糖活性。方法：通过Hantzsch噻唑合成反应制备2-氨基4-甲基噻唑,然后用氯乙酰氯和三乙胺进行氯乙酰化,所得中间体氯乙酰胺经芳基甲胺处理得到目标物,最后,在干燥的乙醚中用氯化氢乙醚溶液处理即可得到目标物的盐酸盐。利用小鼠体内口服葡萄糖耐受量法测定目标化合物在治疗糖尿病方面的活性。结果：合成了21个结构新颖的化合物,结构经过1H-NMR和ESI-MS确认。结论：经过活性测试,发现其中的两个目标化合物具有明显的降血糖作用,其中化合物7f的活性与阳性对照药西他列汀相当,化合物7h的活性则超过阳性对照药,显示了在治疗糖尿病方面的前景。     

D‐420720, A novel orally active sulfonamide compound dipeptidyl peptidase IV inhibitor: structure and activity relationship of arylsulfonamide to dipeptidyl peptidase IV inhibition

Diabetes mellitus is a chronic disease characteristic of poor glucose homeostasis that requires constant monitoring and adjustment of blood glucose levels by exogenous intervention. Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) are two incretin peptide hormones secreted from the intestine to synergize insulin's function at lowering blood glucose. The effects of GLP‐1 or GIP administration are short‐lived because they are rapidly inactivated by circulating dipeptidyl peptidase IV (DPP‐IV). Therefore, DPP‐IV inhibitors have been suggested to be a new class of molecule for treating hyperglycemic conditions in diabetic patients. The recent approval of Merck's Sitagliptin (a DPP‐IV‐specific inhibitor) indicates that DPP‐IV inhibition is a good target for new therapeutic agent development. The present study was conducted to evaluate the efficacies of a series of dipeptidyl derivatives with a sulfonamide moiety as DPP‐IV inhibitors. Among these compounds, D‐420720 was a potent inhibitor (K_i=39 nM), with a selectivity of 9160‐fold over the DPP‐II isozyme and elicits a hypoglycemic effect on oral glucose tolerance test with normal male ICR mice. Drug Dev Res 69: 514–525, 2008. © 2008 Wiley‐Liss, Inc.     

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP‐4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP‐4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose‐lowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP‐4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half‐life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug‐drug interactions. The off‐target inhibition of selective DPP‐4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP‐4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once‐daily dosing. It is unknown if DPP‐4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP‐4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.     

Concentration‐dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice,rats and humans

Objectives The purpose of this study was to characterise the plasma protein binding of BI 1356. Methods BI 1356 (proposed trade name ONDERO) is a novel dipeptidyl peptidase 4 (DPP‐4) inhibitor, which is under clinical development for the treatment of type 2 diabetes. DPP‐4 is expressed in various tissues but soluble DPP‐4 is also present in plasma. Therefore, binding to soluble DPP‐4 may influence the pharmacokinetics of BI 1356. Plasma protein binding of BI 1356 was determined in vitro for wild type mice and rats and the results compared with those for DPP‐4 knockout mice and DPP‐4 deficient Fischer rats. In addition, protein binding of BI 1356 was examined in plasma from healthy human volunteers and renal excretion of the compound in the DPP‐4 knockout mice was compared with that occurring in wild type mice. Key findings The results showed that BI 1356 exhibited a prominent concentration‐dependent plasma protein binding due to a saturable high affinity binding to the DPP‐4 target in plasma. Differences in renal excretion of BI 1356 between DPP‐4 knockout mice and wild type mice suggested that saturable binding of BI 1356 to DPP‐4 in the body also influenced elimination. Conclusions High affinity, but readily saturable binding of BI 1356 to its target DPP‐4 accounted primarily for the concentration‐dependent plasma protein binding at therapeutic plasma concentrations of BI 1356.     

Incretin mimetics and dipeptidyl peptidase 4 inhibitors in clinical trials for the treatment of type 2 diabetes

Background: Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet. Objective: To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin. Method: Review of Phase III clinical trials based on Medline search published up to April 2008. Results: The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 – 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost. Conclusion: Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.     

Fragment‐ and negative image‐based screening of phosphodiesterase 10A inhibitors

A novel virtual screening methodology called fragment‐ and negative image‐based (F‐NiB) screening is introduced and tested experimentally using phosphodiesterase 10A (PDE10A) as a case study. Potent PDE10A‐specific small‐molecule inhibitors are actively sought after for their antipsychotic and neuroprotective effects. The F‐NiB combines features from both fragment‐based drug discovery and negative image‐based (NIB) screening methodologies to facilitate rational drug discovery. The selected structural parts of protein‐bound ligand(s) are seamlessly combined with the negative image of the target's ligand‐binding cavity. This cavity‐ and fragment‐based hybrid model, namely its shape and electrostatics, is used directly in the rigid docking of ab initio generated ligand 3D conformers. In total, 14 compounds were acquired using the F‐NiB methodology, 3D quantitative structure–activity relationship modeling, and pharmacophore modeling. Three of the small molecules inhibited PDE10A at ~27 to ~67 μM range in a radiometric assay. In a larger context, the study shows that the F‐NiB provides a flexible way to incorporate small‐molecule fragments into the drug discovery.     

Inhibition of dipeptidyl peptidase 4 by BI-1356, a new drug for the treatment of beta-cell failure in type 2 diabetes

BI 1356, a xanthine-based DPP-4 inhibitor, has reached Phase III trials. The compound efficiently inhibits dipeptidyl peptidase 4 (DPP-4) in vitro and in vivo. In vivo GLP-1 levels increase to levels at or above the levels of other DPP-4 inhibitors. Preclinical trials suggest a once-daily administration of 5 mg to be efficient, long-lasting and without known side effects.     

Once-weekly dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a systematic review and meta-analysis

Objective: To assess the efficacy and safety of omarigliptin and trelagliptin, novel dipeptidyl peptidase-4 inhibitors administered once-weekly (DPP-4i QW).

Methods: We systematically searched for placebo- and active-controlled randomized trials in adults with type 2 diabetes mellitus.

Results: Fifteen primary studies with 5709 participants were included. DPP-4i QW were more effective than placebo in reducing hemoglobin A_1c (HbA_1c) (Weighted Mean Difference (WMD) ?0.63%; 95% CI ?0.80, ?0.46; I² = 84%) and had a similar glucose-lowering effect with daily DPP-4i (WMD 0.01%; ?0.08, 0.11%; I² = 34%). Omarigliptin was less effective compared with oral antidiabetic agents, other than daily DPP-4i, (WMD 0.24%; 0.10, 0.38; I² = 12%). Omarigliptin did not affect body weight (WMD versus placebo 0.60 kg; 0.25, 0.96; I² = 0%). Risk for any hypoglycemia was similar between DPP-4i QW and placebo (Odds Ratio 1.32; 0.78, 2.22; I² = 0%). Incidence of other adverse events did not differ between DPP-4i QW and control.

Conclusions: DPP-4i QW were superior to placebo and similar to daily DPP-4i in terms of glycemic control, and were not associated with any specific adverse events. There is limited comparative effectiveness evidence against other agents, while their effect on hard clinical safety outcomes is unknown.     

Proposing novel MDM2 inhibitors: Combined physics‐driven high‐throughput virtual screening and in vitro studies

The mouse double minute 2 (MDM2) protein acts as a negative regulator of the p53 tumor suppressor. It directly binds to the N terminus of p53 and promotes p53 ubiquitination and degradation. Since the most common p53‐suppressing mechanisms involve the MDM2, proposing novel inhibitors has been the focus of many in silico and also experimental studies. Thus, here we screened around 500,000 small organic molecules from Enamine database at the binding pocket of this oncogenic target. The screening was achieved systematically with starting from the high‐throughput virtual screening method followed by more sophisticated docking approaches. The initial high number of screened molecules was reduced to 100 hits which then were studied extensively for their therapeutic activity and pharmacokinetic properties using binary QSAR models. The structural and dynamical profiles of the selected molecules at the binding pocket of the target were studied thoroughly by all‐atom molecular dynamics simulations. The free energy of the binding of the hit molecules was estimated by the MM/GBSA method. Based on docking simulations, binary QSAR model results, and free energy calculations, 11 compounds ( E1 – E11 ) were selected for in vitro studies. HUVEC vascular endothelium, colon cancer, and breast cancer cell lines were used for testing the binding affinities of the identified hits and for further cellular effects on human cancer cell. Based on in vitro studies, six compounds ( E1 , E2 , E5 , E6 , E9 , and E11 ) in breast cancer cell lines and six compounds ( E1 , E2 , E5 , E6 , E8 , and E10 ) in colon cancer cell lines were found as active. Our results showed that these compounds inhibit proliferation and lead to apoptosis.     

Pharmacophore‐based virtual screening,molecular docking,molecular dynamics simulation,and biological evaluation for the discovery of novel BRD4 inhibitors

Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors using pharmacophore‐based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules of twelve hits were found to be active in bioactivity tests. Among the molecules, compound 5 exhibited potent anticancer activity, and the IC₅₀ values against human cancer cell lines MV4‐11, A375, and HeLa were 4.2, 7.1, and 11.6 μm , respectively. After that, colony formation assay, cell cycle, apoptosis analysis, wound‐healing migration assay, and Western blotting were carried out to learn the bioactivity of compound 5 .     

Design,Synthesis, Structure–Activity Relationships,and Docking Studies of 1‐(γ‐1,2,3‐Triazol Substituted Prolyl)‐(S)‐3,3‐Difluoropyrrolidines as a Novel Series of Potent and Selective Dipeptidyl Peptidase‐4 Inhibitors

Dipeptidyl peptidase‐4 inhibitors hold great potential for the treatment of type 2 diabetes. A series of 1‐(γ‐1,2,3‐triazol substituted prolyl)‐(S)‐3,3‐difluoropyrrolidines were designed, synthesized, and evaluated as novel dipeptidyl peptidase‐4 inhibitors. Most of the compounds exhibited good in vitro potency against dipeptidyl peptidase‐4. Among these, compounds 7j , 7q, and 7s displayed good dipeptidyl peptidase‐4 activity and excellent selectivity versus other proteases including dipeptidyl peptidase‐8, dipeptidyl peptidase‐9, and FAP. The possible binding modes of compounds 7j , 7q, and 7s with dipeptidyl peptidase‐4 were also explored by molecular docking simulation.     

Tissue distribution of the novel DPP‐4 inhibitor BI 1356 is dominated by saturable binding to its target in rats

BI 1356 (INN: linagliptin) is an inhibitor of dipeptidyl peptidase‐4 (DPP‐4). This study investigated whether saturable binding of BI 1356 to its target DPP‐4 occurs in tissues and whether drug accumulation occurs at these sites in vivo. In order to test these hypotheses, the tissue distribution of BI 1356 was determined in wild‐type and DPP‐4 deficient rats at different dose levels by means of whole body autoradiography and measurement of tissue radioactivity concentrations after single i.v. dosing of [¹⁴C]‐radio labeled BI 1356. The accumulation behavior of drug‐related radioactivity in tissues was further explored in an oral repeat dose study. Tissue levels of [¹⁴C]BI 1356 related radioactivity were markedly lower in all investigated tissues of the DPP‐4 deficient rats and the difference of the dose‐dependent increase of radioactivity tissue levels between both rat strains indicates that tissue distribution at low doses of BI 1356 is dominated by binding of BI 1356 to DPP‐4 in tissues. As the binding to DPP‐4 is strong but reversible, the tissue binding results in a long terminal half‐life in several tissues including plasma. The binding capacity to DPP‐4 is, however, limited. In the rat, saturation of DPP‐4 binding is suggested at an intravenous dose above 0.01–0.1 mg/kg [¹⁴C]BI 1356. As the DPP‐4 binding capacity is saturated already at low doses, accumulation of BI 1356 in tissues is unlikely, despite the long persistence of low amounts in the body. Copyright © 2009 John Wiley & Sons, Ltd.     

Inhibitors of proline-specific dipeptidyl peptidases: DPP IV inhibitors as a novel approach for the treatment of Type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a validated target for the treatment of Type 2 diabetes, with several inhibitors currently in Phase III clinical trials. This review will mainly focus on DPP IV inhibitors that were published in scientific literature and patents after 2002. Medicinal chemistry aspects of several classes of inhibitors are described with respect to inhibitory potency, selectivity over DPP8, DPP9, FAPα and DPP II, stability and ADME/Tox issues. Although the main part of this review is on potent and selective DPP IV inhibitors, selective inhibitors for the related proline-specific dipeptidyl peptidases will be described.     

Design,Synthesis and Biological Evaluation of Imidazo[1,2‐a]pyridine Derivatives as Novel DPP‐4 Inhibitors

A new series of DPP‐4 inhibitors with imidazo[1,2‐a]pyridine scaffold were designed by exploiting scaffold hopping strategy and docking study. Based on docking binding model, structural modifications of 2‐benzene ring and pyridine moieties of compound 5a led to the identification of compound 5d with 2, 4‐dichlorophenyl group at the 2‐position as a potent (IC₅₀ = 0.13 μm ), selective (DPP‐8/DPP‐4 = 215 and DPP‐9/DPP‐4 = 192) and in vivo efficacious DPP‐4 inhibitor. Further, molecular docking revealed that compound 5d could retain key binding features of DPP‐4 with the pyridine moiety of imidazo[1,2‐a]pyridine ring providing an additional π?π interaction with Phe357 of DPP‐4. Compound 5d might be a promising lead for further development of novel DPP‐4 inhibitor treating T2DM.