Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The serine protease dipeptidyl peptidase IV (DPP-IV) is a clinically validated target for the treatment of type II diabetes and has received considerable interest from the pharmaceutical industry over the last years. Concomitant with a large variety of published small molecule DPP-IV inhibitors almost twenty co-crystal structures have been released to the public as of May 2006. In this review, we discuss the structural characteristics of the DPP-IV binding site and use the available X-ray information together with published structure-activity relationship data to identify the molecular interactions that are most important for tight enzyme-inhibitor binding. Optimized interactions with the two key recognition motifs, i.e. the lipophilic S1 pocket and the negatively charged Glu 205/206 pair, result in large gains in binding free energy, which can be further improved by additional favorable contacts to side chains that flank the active site. First examples show that the lessons learned from the X-ray structures can be successfully incorporated into the design of novel DPP-IV inhibitors.
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PMID:Molecular recognition of ligands in dipeptidyl peptidase IV. 1735 81

Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes.
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PMID:Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. 1744 5

Dipeptidyl peptidase 4 (DPP-4) inhibition prevents the rapid degradation of the incretins, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. Incretins have beneficial effects on glycaemic control in patients with type 2 diabetes through their effects on both alpha- and beta-cells in the pancreas and possibly through additional non-pancreatic effects. Vildagliptin is a potent and selective oral DPP-4 inhibitor that has been studied both as monotherapy and in combination with other antidiabetic treatments. This agent has been shown to be well tolerated and is efficacious in reducing glycosylated haemoglobin, fasting plasma glucose and postprandial glucose levels in trials lasting up to 52 weeks. Vildagliptin is weight neutral, does not cause oedema and is associated with a very low incidence of hypoglycaemia. Recently reported clinical data have helped to further clarify the mechanisms of action and effects of vildagliptin. These results suggest that vildagliptin, as a member of the novel class of DPP-4 inhibitors, has the potential to significantly change the clinical management of diabetes. Future research will further define its use in various patient populations and its possible disease-modifying effects.
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PMID:Dipeptidyl peptidase 4 inhibition and vildagliptin therapy for type 2 diabetes. 1759 76

Dipeptidyl peptidase IV (DPP-IV) deactivates the incretin hormones GLP-1 and GIP by cleaving the penultimate proline or alanine from the N-terminal (P1-position) of the peptide. Inhibition of this enzyme will prevent the degradation of the incretin hormones and maintain glucose homeostasis; this makes it an attractive target for the development of drugs for diabetes. This paper reports 3D-QSAR analysis of several DPP-IV inhibitors, which were aligned by the receptor-based technique. The conformation of the molecules in the active site was obtained through docking methods. The QSAR models were generated on two training sets composed of 74 and 25 molecules which included phenylalanine, thiazolidine, and fluorinated pyrrolidine analogs. The 3D-QSAR models are robust with statistically significant r(2), q(2), and r(pred)(2) values. The CoMFA and CoMSIA models were used to design some new inhibitors with several fold higher binding affinity.
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PMID:3D-QSAR studies of Dipeptidyl peptidase IV inhibitors using a docking based alignment. 1767 45

Prolyl, cystyl and pyroglutamyl peptidases are emerging targets for diabetes and cognitive deficit therapies. The present study is focused on the influence of diabetes mellitus induced by streptozotocin on levels of representative hydrolytic activities of these enzymes in the rat hypothalamus and hippocampus. Streptozotocin-diabetic rats presented about 348mg glucose/dL blood, and a slightly increased hematocrit and plasma osmolality. The activities of soluble and membrane-bound dipeptidyl-peptidase IV, and soluble cystyl aminopeptidase did not differ between diabetic and control rats in both brain areas. Hippocampal soluble prolyl oligopeptidase presented similar activities between diabetic and controls. Increased activities in diabetics were observed for soluble prolyl oligopeptidase (1.78-fold) and membrane-bound cystyl aminopeptidase (2.55-fold) in the hypothalamus, and for membrane-bound cystyl aminopeptidase (5.14-fold) in the hippocampus. In both brain areas, the activities of membrane-bound and soluble pyroglutamyl aminopeptidase were slightly lower (<0.7-fold) in diabetics. All modifications (except hematocrit) observed in streptozotocin-treated rats were mitigated by the administration of insulin. Glucose and/or insulin were shown to alter in vitro the hypothalamic activities of soluble pyroglutamyl aminopeptidase and prolyl oligopeptidase, as well as membrane-bound cystyl aminopeptidase. These data provide the first evidence that diabetes mellitus generates direct and indirect effects on the activity levels of brain peptidases. The implied regional control of regulatory peptide activity by these peptidases suggests novel potential approaches to understand certain disruptions on mediator and modulatory functions in diabetes mellitus.
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PMID:Prolyl, cystyl and pyroglutamyl peptidase activities in the hippocampus and hypothalamus of streptozotocin-induced diabetic rats. 1769 48

Neutral endopeptidase (NEP) is the major enzyme involved in the metabolic inactivation of a number of bioactive peptides including the enkephalins, substance P, endothelin, bradykinin and atrial natriuretic factor, as well as the incretin hormone glucagon-like peptide 1 (GLP-1), which is a potent stimulator of insulin secretion. The activity of GLP-1 is also rapidly abolished by the serine protease dipeptidyl peptidase IV (DPP-IV), which led to an elevated interest in inhibitors of this enzyme for the treatment of type II diabetes. A dual NEP/DPP-IV inhibitor concept is proposed, offering an alternative strategy for the treatment of type 2 diabetes. Here, the synthesis and crystal structures of the soluble extracellular domain of human NEP (residues 52-749) complexed with the NEP, competitive and potent dual NEP/DPP-IV inhibitor MCB3937 are described.
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PMID:Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV. 1770 66

Approximately two thirds of patients with type 2 diabetes mellitus (T2DM) are unable to reach the hemoglobin A(1c) target set by the American Diabetes Association (HbA(1c) <7.0%). Therefore, T2DM continues to be a major public health concern. Incretin mimetics and dipeptidyl peptidase IV inhibitors are medications that have the potential to improve patients' glycemic control, as well as to result in beneficial socioeconomic effects. Research suggests that significant benefits are to be gained from incretin mimetics and dipeptidyl peptidase IV inhibitors, either one used as monotherapy or used together as combination therapy. However, the benefits and risks of these agents need to be evaluated more thoroughly, with emphasis on such adverse effects as edema, hypoglycemia, and weight gain.
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PMID:Application of incretin mimetics and dipeptidyl peptidase IV inhibitors in managing type 2 diabetes mellitus. 1772 13

Many patients with type 2 diabetes mellitus (T2DM) are unable to achieve adequate glycemic control. Of the approximately 19 million individuals with T2DM in the United States, only about a third achieve the hemoglobin A(1c) (HbA(1c)0 goal set forth by the American Diabetes Association (HbA(1c) <7% [6% if it can be achieved safely]). The incretin mimetics are a new class of medications available for treating patients with T2DM. They mimic the action of incretins, which are peptide hormones that originate in the gastrointestinal tract. The two major incretins in humans are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are released during nutrient absorption, augmenting insulin secretion. However, incretins are susceptible to degradation by dipeptidyl peptidase IV (DPP-IV). Dipeptidyl peptidase IV inhibitors suppress the degradation of incretins, thus extending the activity of GLP-1 and GIP. The glycemic profiles of patients after administration of incretin mimetics and DPP-IV inhibitors show improvement in postprandial glucose levels and ultimately in HbA(1c). Therefore, incretin mimetics and DPP-IV inhibitors may play a clinically significant role in the treatment of patients with T2DM.
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PMID:The pathophysiologic role of incretins. 1772 14

Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new pharmacological class of drugs for treating Type 2 diabetes. They improve the capacity of the organism to control glycemia by increasing the levels of active incretins. Their mechanism of action is thus radically different from those of other anti-diabetic drugs currently available. DDP-4 inhibitors use a physiological mechanism to control hyperglycemia, by stimulating the secretion of insulin from beta-cells, decreasing the secretion of glucagon from pancreatic alpha-cells, and at the same time reducing the production of glucose by the liver. DDP-4 inhibitors have shown significant efficacy in maintaining reduced levels of glycosylated hemoglobin for up to 1 year. In vitro and animal studies have shown that they can inhibit apoptosis of beta-cells and favor their regeneration and differentiation. The oral DPP-4 inhibitors vildagliptin, sitagliptin, and saxagliptin are efficacious both alone and in association with other oral anti-diabetic agents and may be administered in a single daily dose. Lastly, they have substantial advantages with respect to other anti-diabetic drugs, since they involve a low risk of hypoglycemia and do not affect body weight.
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PMID:Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management. 1784 46

Current type 2 diabetes therapies are mainly targeted at stimulating pancreatic beta-cell secretion and reducing insulin resistance. A number of alternative therapies are currently being developed to take advantage of the actions of the incretin hormones Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP). These hormones are released from the small intestine in response to nutrient ingestion and stimulate insulin secretion in a glucose-dependent manner. One approach to potentiating their actions is based on inhibiting dipeptidyl peptidase IV (DPP IV), the major enzyme responsible for degrading the incretins in vivo. DPP IV exhibits characteristics that have allowed the development of specific orally administered inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes. A number of clinical trials have demonstrated that DPP IV inhibitors are effective in improving glucose disposal and reducing hemoglobin A1c levels in type 2 diabetic patients and one inhibitor, sitagliptin, is now in therapeutic use, with others likely to receive FDA approval in the near future. Studies aimed at elucidating the mode of action of the inhibitors are still ongoing. Both enhancement of insulin secretion and reduction in glucagon secretion, resulting from the blockade of incretin degradation, are believed to play important roles in DPP IV inhibitor action. Preclinical studies indicate that increased levels of incretins improve beta-cell secretory function and exert effects on beta-cell mitogenesis and survival that can preserve beta-cell mass. Roles for other hormones, neuropeptides and cytokines in DPP IV inhibitor-medicated responses are also possible.
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PMID:Dipeptidyl peptidase IV inhibitors and diabetes therapy. 1798 65


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