piperidines and mitiglinide

Glinides, including repaglinide, nateglinide and mitiglinide, are a type of fasting insulin secretagogue that could help to mimic early-phase insulin release, thus providing improved control of the postprandial glucose levels. Glinides stimulate insulin secretion by inhibiting ATP-sensitive potassium channels in the pancreatic β-cell membrane. Although glinides have been widely used clinically and display excellent safety and efficacy, the response to glinides varies among individuals, which is partially due to genetic factors involved in drug absorption, distribution, metabolism and targeting. Several pharmacogenomic studies have demonstrated that variants of genes involved in the pharmacokinetics or pharmacodynamics of glinides are associated with the drug response. Polymorphisms of genes involved in drug metabolism, such as CYP2C9, CYP2C8 and SLCO1B1, may influence the efficacy of glinides and the incidence of adverse effects. In addition, Type 2 diabetes mellitus susceptibility genes, such as KCNQ1, PAX4 and BETA2, also influence the efficacy of glinides. In this article, we review and discuss current pharmacogenomics researches on glinides, and hopefully provide useful data and proof for clinical application.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Inactivation, Metabolic; Insulin; Insulin Secretion; Insulin-Secreting Cells; Isoindoles; KATP Channels; Nateglinide; Pharmacogenetics; Phenylalanine; Piperidines

Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses.. Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug.. Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values.. Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.

Topics: Animals; ATP-Binding Cassette Transporters; Carbamates; Cardiovascular Diseases; Cricetinae; Cyclohexanes; Diabetes Mellitus, Type 2; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Ischemic Preconditioning, Myocardial; Isoindoles; Mice; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nateglinide; Phenylalanine; Piperidines; Potassium Channels, Inwardly Rectifying; Rats; Receptors, Drug; Risk Factors; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide

Topics: Adenosine Triphosphate; Animals; ATP-Binding Cassette Transporters; Calcium Channels; Carbamates; Cyclohexanes; Exocytosis; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Islets of Langerhans; Isoindoles; Nateglinide; Organ Specificity; Phenylalanine; Piperidines; Potassium Channels; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Receptors

The loss of early insulin secretion appears to be a critical event in the deterioration in glucose tolerance during the development of type 2 diabetes. There is therefore a strong rationale for developing new antidiabetic agents aimed at restoring or replacing early prandial insulin secretion and thereby curbing mealtime glucose excursions in patients with type 2 diabetes. Four such new agents are either now available (repaglinide and nateglinide) or in clinical development (KAD-1229 and BTS 67 582). Preclinical studies suggest that each of these new insulinotropic agents share a common receptor/effector mechanism with the sulfonylureas (SUs) but that each may have distinct characteristics that differentiate them from the SUs and from each other. Nateglinide and KAD-1229 clearly stimulate biphasic insulin secretion in vitro and in vivo and their effects are rapidly reversible, whereas the effects of repaglinide and BTS 67 582 are prolonged well beyond their removal from perfusion media in vitro or their clearance in vivo. Available data from human studies indicate that the pharmacokinetics of repaglinide and nateglinide are similar, i.e., they are both rapidly absorbed and eliminated, but consistent with findings from animal studies, the insulinotropic and glucose-lowering effects of repaglinide are slower in onset and more prolonged than those of nateglinide. Repaglinide and nateglinide have been shown to be safe and well-tolerated in patients with type 2 diabetes and to produce clinically-meaningful reductions of HbA1c, both alone and in combination with agents with complementary modes of action (e.g., metformin and thiazolidinediones). Because these new agents can potentially bring patients to near normoglycemia without an undue risk of hypoglycemia, they are important additions to the therapeutic armamentarium.

Topics: Animals; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glucose; Guanidines; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Piperidines

Glycemic variability is a risk factor for total death and cardiovascular events. There are no obvious guidelines for the direct treatment of glycemic variability, but it can be improved with the treatment of postprandial hyperglycemia.. We compared the effect of repaglinide versus the combination of mitiglinide and voglibose, used to improve postprandial hyperglycemia, on glycemic variability in Japanese patients with type 2 diabetes.. We performed an open-label randomized cross-over trial between April 2016 and April 2018. Patients with type 2 diabetes who were admitted to our hospital were enrolled in our study (n = 12). Glycemic variability. was assessed using a continuous glucose monitoring system.. The average glucose level of the repaglinide phase (146.1 ± 20.7 mg/dl) and the combination of mitiglinide and voglibose phase (132.3 ± 19.8 mg/dl) were similar (P = 0.10). The standard division (P = 0.0005), coefficient of variation (P = 0.006), and mean amplitude of glycemic excursion (P = 0.002) of glucose were lower in the combination of mitiglinide and voglibose phase than in the repaglinide phase.. Treatment with the combination of mitiglinide and voglibose might be more effective than repaglinide for the improvement of glycemic variability.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Inositol; Isoindoles; Japan; Piperidines

One adverse effect of methylprednisolone (MP) pulse therapy is an acute dose-dependent increase in the blood glucose level. Five patients with thyroid ophthalmopathy but normal glucose tolerance received MP pulse therapy (3 cycles, 3 days/week) and were assessed by continuous glucose monitoring. Steroid therapy increased the mean sensor glucose level, and all patients developed steroid-induced diabetes. The patients were treated alternately with mitiglinide (30 mg/day) and repaglinide (1.5 mg/day) during the second or third MP pulse therapy. The sensor glucose levels before lunch and dinner were more favorable during treatment with repaglinide than during treatment with mitiglinide. Repaglinide may be more clinically appropriate than mitiglinide.

Topics: Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Graves Ophthalmopathy; Humans; Hyperglycemia; Hypoglycemic Agents; Isoindoles; Male; Methylprednisolone; Middle Aged; Piperidines; Treatment Outcome

Many patients with type 2 diabetes mellitus(T2DM) do not achieve satisfactory glycemic control by monotherapy alone, and often require multiple oral hypoglycemic agents (OHAs). Combining OHAs with complementary mechanisms of action is fundamental to the management of T2DM. Fixed-dose combination therapy(FDC) offers a method of simplifying complex regimens. Efficacy and tolerability appear to be similar between FDC and treatment with individual agents. In addition, FDC can enhance adherence and improved adherence may result in improved glycemic control. Four FDC agents are available in Japan: pioglitazone-glimepiride, pioglitazone-metformin, pioglitazone-alogliptin, and voglibose-mitiglinide. In this review, the advantages and disadvantages of these four combinations are identified and discussed.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Inositol; Isoindoles; Metformin; Pioglitazone; Piperidines; Sulfonylurea Compounds; Thiazolidinediones; Uracil

To design and synthesize new compounds of prandial glucose regulator with more simple structure.. The target compounds were synthesized from diethyl succinate and benzaldehyde or 4-fluorobenzaldehyde by four-step reactions. Thus 18 compounds were synthesized. Their structures were comfirmed by NMR, MS and IR.. Seventeen compounds had different hypoglycemic activity in mice, among them, 9 compounds had higher hypoglycemic activity and 6 compounds had character of prandial glucose regulator.. Part of the compounds have higher hypoglycemic activity deserve to be further investigated.

Topics: Animals; Benzylidene Compounds; Blood Glucose; Carbamates; Cyclohexanes; Hypoglycemic Agents; Indoles; Isoindoles; Mice; Molecular Structure; Nateglinide; Phenylalanine; Piperidines; Structure-Activity Relationship; Succinates

We investigated the in vitro effects of therapeutical concentrations of S 21403 (a succinic acid derivative also known as KAD 1229 and mitiglinide) on insulin and glucagon secretion during a metabolic stimulus (glucose rising from 5 to 8.33 mM) or at a stable 2.22 mM glucose using the isolated perfused rat pancreas model, and we compared them with the patterns of repaglinide and glibenclamide. Control perfusions were also performed. During 8.33 mM glucose, insulin release peaked to 339.12+/-22.87 microU/ml in controls. S 21403 enhanced insulin release (first peak 413.02+/-14.90 microU/ml; P<0.03 vs. controls, P=ns vs. repaglinide, P<0.005 vs. glibenclamide). Repaglinide increased glucose-induced first peak secretion to 409.33+/-20.05 microU/ml within the eighth minute (P<0.05 vs. controls, P<0.01 vs. glibenclamide). Glibenclamide did not affect the first phase of glucose-induced insulin release (peak of 338.41+/-29.79 microU/ml) but potentiated and delayed the second phase. No drug affected glucagon release. In conclusion, S 21403 induces a faster, more physiological pattern of insulin release than the other drugs we tested.

Topics: Animals; Carbamates; Dose-Response Relationship, Drug; Glucose; Glyburide; Hypoglycemic Agents; In Vitro Techniques; Indoles; Insulin; Insulin Secretion; Isoindoles; Male; Pancreas; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

1. Hypoglycaemia-inducing sulphonylureas, such as glibenclamide, inhibit cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels. In search of modulators of CFTR, we investigated the effects of the non-sulphonylurea hypoglycaemic agents meglitinide, repaglinide, and mitiglinide (KAD-1229) on CFTR Cl- channels in excised inside-out membrane patches from C127 cells expressing wild-type human CFTR. 2. When added to the intracellular solution, meglitinide and mitiglinide inhibited CFTR Cl- currents with half-maximal concentrations of 164+/-19 microM and 148+/-36 microM, respectively. However, repaglinide only weakly inhibited CFTR Cl- currents. 3. To understand better how non-sulphonylurea hypoglycaemic agents inhibit CFTR, we studied single channels. Channel blockade by both meglitinide and mitiglinide was characterized by flickery closures and a significant decrease in open probability (Po). In contrast, repaglinide was without effect on either channel gating or Po, but caused a small decrease in single-channel current amplitude. 4. Analysis of the dwell time distributions of single channels indicated that both meglitinide and mitiglinide greatly decreased the open time of CFTR. Mitiglinide-induced channel closures were about 3-fold longer than those of meglitinide. 5. Inhibition of CFTR by meglitinide and mitiglinide was voltage-dependent: at positive voltages channel blockade was relieved. 6. The data demonstrate that non-sulphonylurea hypoglycaemic agents inhibit CFTR. This indicates that these agents have a wider specificity of action than previously recognized. Like glibenclamide, non-sulphonylurea hypoglycaemic agents may inhibit CFTR by occluding the channel pore and preventing Cl- permeation.

Topics: Adenosine Triphosphate; Animals; Benzamides; Carbamates; Cell Line; Chloride Channels; Cyclic AMP-Dependent Protein Kinases; Cystic Fibrosis Transmembrane Conductance Regulator; Electric Conductivity; Epithelial Cells; Glyburide; Humans; Hypoglycemic Agents; Indoles; Ion Channel Gating; Isoindoles; Kinetics; Mice; Patch-Clamp Techniques; Piperidines; Sulfonylurea Compounds; Transfection

The insulinotropic action of the meglitinide analogues KAD-1229, A-4166 and repaglinide was examined in rat pancreatic islets deprived of exogenous nutrient or incubated in the presence of nutrient secretagogues such as D-glucose and the methyl esters of pyruvic acid, succinic acid and glutamic acid. The meglitinide analogues exerted little effect on insulin release in the absence of exogenous nutrient or in the presence of methyl pyruvate. They caused obvious stimulation of insulin output in the presence of D-glucose, dimethyl succinate or dimethyl glutamate. It is proposed, therefore, that suitable esters of dicarboxylic nutrients could be used to potentiate the secretory response to meglitinide analogues in non-insulin-dependent diabetes mellitus.

Topics: Animals; Carbamates; Cells, Cultured; Cyclohexanes; Glucose; Glutamates; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Islets of Langerhans; Isoindoles; Nateglinide; Phenylalanine; Piperidines; Pyruvates; Rats; Succinates

Non-sulfonylurea hypoglycemic agents of the meglitinide family such as S3075, repaglinide, KAD-1229, and A-4166, were found to display a comparable U-shaped conformation by molecular modelling, with hydrophobic cycles placed at the extremity of each branch and a peptidic bond placed at the bottom of the U. A comparable conformation was observed with the hypoglycemic sulfonylureas glibenclamide and glimepiride. A different conformation with a greater distance between the hydrophobic cycles at the extremity of each branch was found, however, with the biologically inactive enantiomers of A-4166 and repaglinide and the poorly efficient insulinotropic agent meglitinide. The identification of a common conformation of these hypoglycemic agents may help in the design of highly active compounds and provide an imprint of their postulated target receptor on the pancreatic B-cell plasma membrane.

Topics: Benzamides; Carbamates; Cyclohexanes; Drug Design; Glyburide; Hypoglycemic Agents; Indoles; Isoindoles; Molecular Conformation; Nateglinide; Phenylalanine; Piperidines; Stereoisomerism; Structure-Activity Relationship; Sulfonylurea Compounds

At normal extracellular K+ concentration (5 mM), the meglitinide analogues A-4166, KAD-1229, repaglinide and S3075, all tested at a 10 mu M concentration, markedly enhanced insulin release evoked by 6 mM D-glucose in isolated rat pancreatic islets. They failed, however, to augment the much higher rate of insulin release evoked by D-glucose in islets exposed to a high K+ concentration (30 mM). Under the latter conditions, the potent diazoxide analogue BPDZ-44 (50 mu M) did not exert any sizeable effect upon insulin release. Even at normal K+ concentration, BPDZ-44 (50 mu M), which suppressed glucose-stimulated insulin release, only caused a partial inhibition of the insulinotropic action of A-4166 and failed to affect significantly insulin secretion in the presence of KAD-1229, repaglinide or S3075. These findings argue against the view that meglitinide analogues could affect cytosolic Ca2+ activity independently of the closing of ATP-sensitive K+ channels. The present results also indicate that, with the possible exception of A-4166 which in the least potent secretagogue in this series, meglitinide analogues are able, like hypoglycemic sulphonylureas, to fully protect ATP-sensitive K+ channels against their activation by BPDZ-44.

Topics: Animals; Benzamides; Carbamates; Cyclohexanes; Female; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Islets of Langerhans; Isoindoles; Nateglinide; Phenylalanine; Piperidines; Potassium; Rats

The sodium and calcium ionophoretic activity of meglitinide and three of its hypoglycemic analogs, namely S3075, KAD-1229 and repaglinide was examined in an artificial membrane model. All agents were able to cause the translocation of 45Ca and 22Na from an aqueous solution into an immiscible organic phase. The results were compatible with the formation of a calcium-ionophore complex with a 1-2 stoichiometry. The ionophoretic activity ranged in the following hierarchy: KAD-1229 > S3075 > repaglinide = meglitinide and, hence, did not closely parallel the insulinotropic potential of these non-sulfonylurea hypoglycemic agents. It is proposed, therefore, that the ionophoretic capacity of meglitinide analogs may not represent an essential determinant of their insulin-releasing action.

Topics: Benzamides; Biological Transport; Calcium; Carbamates; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Ionophores; Isoindoles; Membranes, Artificial; Models, Biological; Piperidines; Sodium; Structure-Activity Relationship

The insulinotropic action of meglitinide was compared to that of its analogs S 3075, A-4166, KAD-1229 and repaglinide. None of these hypoglycemic agents significantly enhanced insulin output from rat pancreatic islets incubated for 90 min in the absence of exogenous nutrient. However, all these agents, when tested at a 10 microM concentration, augmented insulin release evoked by either 7 mM D-glucose or 10 microM succinic acid monomethyl ester (SAM). In this respect, meglitinide was a less efficient secretagogue than the other non-sulfonylurea hypoglycemic agents. Moreover, in the presence of 7 mM D-glucose, the lowest concentration of the drug required to cause a significant increase in insulin output decreased from about 1.0 microM for meglitinide to 0.1 microM with A-4166, KAD-1229 or repaglinide and even close to 10 nM in the case of S 3075. The concentration-response relationship thus yielded the following hierarchy, S 3075 > KAD-1229 = repaglinide > A-4166 > meglitinide, there being a difference of more than two orders of magnitude between the weakest and most potent agent.

Topics: Animals; Benzamides; Carbamates; Cyclohexanes; Female; Glucose; Hypoglycemic Agents; In Vitro Techniques; Indoles; Insulin; Insulin Secretion; Islets of Langerhans; Isoindoles; Molecular Structure; Nateglinide; Phenylalanine; Piperidines; Rats; Structure-Activity Relationship; Succinates