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DPP-IV Inhibitors (dpp-iv + inhibitor)

Distribution by Scientific Domains

Medical Sciences	71%
Chemistry	28%

Selected Abstracts

DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue

DIABETES OBESITY & METABOLISM, Issue 4 2009
K. Kos
Context:, Dipeptidyl peptidase IV (DPP-IV) inactivates the incretin hormone glucagon-like peptide. It can also affect the orexigenic hormone neuropeptide Y (NPY1,36) which is truncated by DPP-IV to NPY3,36, as a consequence NPY's affinity changes from receptor Y1, which mediates the antilipolytic function of NPY, to other NPY receptors. Little is known whether DPP-IV inhibitors for the treatment of type 2 diabetic (T2DM) patients could influence these pathways. Aims:, To investigate the in vitro effects of NPY with DPP-IV inhibition in isolated abdominal subcutaneous (AbdSc) adipocytes on fat metabolism, and assessment of NPY receptor and DPP-IV expression in adipose tissue (AT). Methods:,Ex vivo human AT was taken from women undergoing elective surgery (body mass index: 27.5 (mean ± s.d.) ± 5 kg/m2, age: 43.7 ± 10 years, n = 36). Isolated AbdSc adipocytes were treated with human recombinant (rh)NPY (1,100 nM) with and without DPP-IV inhibitor (1 M); glycerol release and tissue distribution of DPP-IV, Y1 and Y5 messenger RNA (mRNA) were measured and compared between lean and obese subjects. Results and conclusion:, rhNPY reduced glycerol release, an effect that was further enhanced by co-incubation with a DPP-IV inhibitor [control: 224 (mean ± s.e.) ± 37 ,mol/l; NPY, 100 nM: 161 ± 27 ,mol/l**; NPY 100 nM/DPP-IV inhibitor, 1 M: 127 ± 14 ,mol/l**; **p < 0.01, n = 14]. DPP-IV was expressed in AbdSc AT and omental AT with relative DPP-IV mRNA expression lower in AbdSc AT taken from obese [77 ± 6 signal units (SU)] vs. lean subjects (186 ± 29 SU*, n = 10). Y1 was predominantly expressed in fat and present in all fat depots but higher in obese subjects, particularly the AbdSc AT-depot (obese: 1944 ± 111 SU vs. lean: 711 ± 112 SU**, n = 10). NPY appears to be regulated by AT-derived DPP-IV. DPP-IV inhibitors augment the antilipolytic effect of NPY in AT. Further studies are required to show whether this explains the lack of weight loss in T2DM patients treated with DPP-IV inhibitors. [source]

LC-MS/MS determination of 2-(4-((2-(2S,5R)-2-Cyano-5-ethynyl-1-pyrrolidinyl)-2-oxoethylamino)-4-methyl-1-piperidinyl)-4-pyridinecarboxylic acid (ABT-279) in dog plasma with high-throughput protein precipitation sample preparation

BIOMEDICAL CHROMATOGRAPHY, Issue 11 2007
Joseph Kim
Abstract As an effective DPP-IV inhibitor, 2-(4-((2-(2S,5R)-2-Cyano-5-ethynyl-1-pyrrolidinyl)-2-oxoethylamino)-4-methyl-1-piperidinyl)-4-pyridinecarboxylic acid (ABT-279), is an investigational drug candidate under development at Abbott Laboratories for potential treatment of type 2 diabetes. In order to support the development of ABT-279, multiple analytical methods for an accurate, precise and selective concentration determination of ABT-279 in different matrices were developed and validated in accordance with the US Food and Drug Administration Guidance on Bioanalytical Method Validation. The analytical method for ABT-279 in dog plasma was validated in parallel to other validations for ABT-279 determination in different matrices. In order to shorten the sample preparation time and increase method precision, an automated multi-channel liquid handler was used to perform high-throughput protein precipitation and all other liquid transfers. The separation was performed through a Waters YMC ODS-AQ column (2.0 × 150 mm, 5 µm, 120 Å) with a mobile phase of 20 mm ammonium acetate in 20% acetonitrile at a flow rate of 0.3 mL/min. Data collection started at 2.2 min and continued for 2.0 min. The validated linear dynamic range in dog plasma was between 3.05 and 2033.64 ng/mL using a 50 µL sample volume. The achieved r2 coefficient of determination from three consecutive runs was between 0.998625 and 0.999085. The mean bias was between ,4.1 and 4.3% for all calibration standards including lower limit of quantitation. The mean bias was between ,8.0 and 0.4% for the quality control samples. The precision, expressed as a coefficient of variation (CV), was ,4.1% for all levels of quality control samples. The validation results demonstrated that the high-throughput method was accurate, precise and selective for the determination of ABT-279 in dog plasma. The validated method was also employed to support two toxicology studies. The passing rate was 100% for all 49 runs from one validation study and two toxicology studies. Copyright © 2007 John Wiley & Sons, Ltd. [source]

ChemInform Abstract: The Asymmetric Synthesis of Sitagliptin, a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes.

CHEMINFORM, Issue 41 2010
Feng Liu
Abstract Key step in the improved synthetic pathway to sitagliptin (VII), a new DPP-IV inhibitor for the treatment of type 2 diabetes mellitus, is an asymmetric Michael addition to give intermediate (IV). [source]

DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue

Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug

DIABETES OBESITY & METABOLISM, Issue 2 2007
Iskandar Idris
Exploiting the incretin effect to develop new glucose-lowering treatments has become the focus of intense research. One successful approach has been the development of oral inhibitors of dipeptidyl peptidase-IV (DPP-IV). These drugs reversibly block DPP-IV-mediated inactivation of incretin hormones, for example, glucagon-like peptide 1 (GLP-1) and also other peptides that have alanine or proline as the penultimate N-terminal amino acid. DPP-IV inhibitors, therefore, increase circulating levels and prolong the biological activity of endogenous GLP-1, but whether this is sufficient to fully explain the substantial reduction in haemoglobin A1c (HbA1c) and associated metabolic profile remains open to further investigation. DPP-IV inhibitors such as vildagliptin and sitagliptin have been shown to be highly effective antihyperglycaemic agents that augment insulin secretion and reduce glucagon secretion via glucose-dependent mechanisms. This review summarizes the major clinical trials with DPP-IV inhibitors as monotherapy and as add-on therapy in patients with type 2 diabetes. The magnitude of HbA1c reduction with DPP-IV inhibitors depends upon the pretreatment HbA1c values, but there seems to be no change in body weight, and very low rates of hypoglycaemia and gastrointestinal disturbance with these agents. DPP-IV inhibitors represent a major new class of oral antidiabetic drug and their metabolic profile offers a number of unique clinical advantages for the management of type 2 diabetes. [source]

Incretins and other peptides in the treatment of diabetes

DIABETIC MEDICINE, Issue 3 2007
J. F. Todd
Abstract Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone, released postprandially, which stimulates insulin secretion and insulin gene expression as well as pancreatic B-cell growth. Together with glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect which is the augmentation of insulin secretion following oral administration of glucose. Patients with Type 2 diabetes have greatly impaired or absent incretin-mediated insulin secretion which is mainly as a result of decreased secretion of GLP-1. However, the insulinotropic action of GLP-1 is preserved in patients with Type 2 diabetes, and this has encouraged attempts to treat Type 2 diabetic patients with GLP-1. GLP-1 also possesses a number of potential advantages over existing agents for the treatment of Type 2 diabetes. In addition to stimulating insulin secretion and promoting pancreatic B-cell mass, GLP-1 suppresses glucagon secretion, delays gastric emptying and inhibits food intake. Continuous intravenous and subcutaneous administration significantly improves glycaemic control and causes reductions in both HbA1c and body weight. However, GLP-1 is metabolized extremely rapidly in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). This is the probable explanation for the short-lived effect of single doses of native GLP-1, making it an unlikely glucose-lowering agent. The DPP-IV resistant analogue, exenatide, has Food and Drug Administration (FDA) approval for the treatment of Type 2 diabetes and selective DPP-IV inhibitors are under development. Both approaches have demonstrated remarkable efficacy in animal models and human clinical studies. Both are well tolerated and appear to have advantages over current therapies for Type 2 diabetes, particularly in terms of the effects on pancreatic B-cell restoration and potential weight loss. [source]

The backbone of oral glucose-lowering therapy: time for a paradigm shift?

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2009
Jochen Seufert
Abstract The complex array of metabolic abnormalities associated with type 2 diabetes provides a number of new targets for therapeutic intervention. Although the established oral glucose-lowering therapies, metformin and the sulfonylureas, continue to provide the backbone of therapeutic approaches, the thiazolidinediones (TZDs) also play an important role. Further, a new class of oral agents, the dipeptidyl peptidase-IV (DPP-IV) inhibitors, has recently become available with apparent utility in decreasing postprandial glucose excursions. This review examines how the TZDs and the DPP-IV inhibitors might integrate into current treatment strategies, considering not only glycemic goals, but also longer-term benefits such as durability of glycemic control, effect on metabolic parameters and cardiovascular outcomes. A practical approach is taken, reflecting potential clinical situations in which therapeutic intervention is required. [source]