nateglinide and meglitinide

The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether insulin secretagogues (sulphonylureas and meglitinide analogues) are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown.. To assess the effects of insulin secretagogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these.. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was April 2016.. We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing insulin secretagogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these.. Two review authors read all abstracts and full-text articles/records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We carried out trial sequential analyses (TSAs) for all outcomes that could be meta-analysed. We assessed the overall quality of the evidence by using the GRADE instrument.. We included six RCTs with 10,018 participants; 4791 participants with data on allocation to intervention groups were randomised to a second- or third-generation sulphonylurea or a meglitinide analogue as monotherapy and 29 participants were randomised to a second-generation sulphonylurea plus metformin. Three trials investigated a second-generation sulphonylurea, two trials investigated a third-generation sulphonylurea and one trial a meglitinide analogue. A total of 4873 participants with data on allocation to control groups were randomised to a comparator group; 4820 participants were randomised to placebo, 23 to diet and exercise, and 30 participants to metformin monotherapy. One RCT of nateglinide contributed 95% of all participants. The duration of the intervention varied from six months to five years. We judged none of the included trials as at low risk of bias for all 'Risk of bias' domains.All-cause and cardiovascular mortality following sulphonylurea (glimepiride) treatment were rarely observed (very low-quality evidence). The RR for incidence of T2DM comparing glimepiride monotherapy with placebo was 0.75; 95% CI 0.54 to 1.04; P = 0.08; 2 trials; 307 participants; very low-quality evidence. One of the trials reporting on the incidence of T2DM did not define the diagnostic criteria used. The other trial diagnosed T2DM as two consecutive fasting blood glucose values ≥ 6.1 mmol/L. TSA showed that only 4.5% of the diversity-adjusted required information size was accrued so far. No trial reported data on serious adverse events, non-fatal myocardial infarction (MI), non-fatal stroke, congestive heart failure (HF), health-related quality of life or socioeconomic effects.One trial with a follow-up of five years compared a meglitinide analogue (nateglinide) with placebo. A total of 310/4645 (6.7%) participants allocated to nateglinide died compared with 312/4661 (6.7%) participants allocated to placebo (hazard ratio (HR) 1.00; 95% CI 0.85 to 1.17; P = 0.98; moderate-quality evidence). The two main criteria for diagnosing T2DM were a fasting plasma glucose level ≥ 7.0 mmol/L or a 2-hour post challenge glucose ≥ 11.1 mmol/L. T2DM developed in 1674/4645 (36.0%) participants in the nateglinide group and in 1580/4661 (33.9%) in the placebo group (HR 1.07; 95% CI 1.00 to 1.15; P = 0.05; moderate-quality evidence). One or more serious adverse event was reported in 2066/4602 (44.9%) participants allocated to nateglinide compared with 2089/4599 (45.6%) participan. There is insufficient evidence to demonstrate whether insulin secretagogues compared mainly with placebo reduce the risk of developing T2DM and its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Topics: Adult; Benzamides; Blood Glucose; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Fasting; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Metformin; Middle Aged; Nateglinide; Phenylalanine; Randomized Controlled Trials as Topic; Sulfonylurea Compounds

The recent Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial reported that nateglinide, a non-sulfonylurea insulin secretagogue, failed to prevent progression from impaired glucose tolerance to diabetes. In order to determine the beneficial effect of insulin secretagogues as a class in diabetes prevention, we performed a literature search for randomized controlled studies and review articles on diabetes prevention and use of sulfonylureas, nateglinide, and meglitinide in PubMed and Ovid Medline since 1950. Three studies were identified with none of them reporting success in preventing diabetes, indicating that insulin secretagogues should not be recommended for diabetes prevention.

Topics: Benzamides; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Disease Progression; Evidence-Based Medicine; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Nateglinide; Phenylalanine; Preventive Health Services; Sulfonylurea Compounds; Treatment Outcome

In type 2 diabetes mellitus, impairment of insulin secretion is an important component of the disease. Meglitinide analogues are a class of oral hypoglycaemic agents that increase insulin secretion, in particular, during the early phase of insulin release.. The aim of this review was to assess the effects of meglitinide analogues in patients with type 2 diabetes mellitus.. We searched several databases including The Cochrane Library, MEDLINE and EMBASE. We also contacted manufacturers and searched ongoing trials databases, and the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) websites.. We included randomised controlled, parallel or cross-over trials comparing at least 10 weeks of treatment with meglitinide analogues to placebo, head-to-head, metformin or in combination with insulin.. Two authors independently extracted data and assessed trial quality.. Fifteen trials involving 3781 participants were included. No studies reported the effect of meglitinides on mortality or morbidity. In the eleven studies comparing meglitinides to placebo, both repaglinide and nateglinide resulted in a reductions in glycosylated haemoglobin (0.1% to 2.1% reduction in HbA1c for repaglinide; 0.2% to 0.6% for nateglinide). Only two trials compared repaglinide to nateglinide (342 participants), with greater reduction in glycosylated haemoglobin in those receiving repaglinide. Repaglinide (248 participants in three trials) had a similar degree of effect in reducing glycosylated haemoglobin as metformin. Nateglinide had a similar or slightly less marked effect on glycosylated haemoglobin than metformin (one study, 355 participants). Weight gain was generally greater in those treated with meglitinides compared with metformin (up to three kg in three months). Diarrhoea occurred less frequently and hypoglycaemia occurred more frequently but rarely severely enough as to require assistance.. Meglitinides may offer an alternative oral hypoglycaemic agent of similar potency to metformin, and may be indicated where side effects of metformin are intolerable or where metformin is contraindicated. However, there is no evidence available to indicate what effect meglitinides will have on important long-term outcomes, particularly mortality.

Topics: Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines; Randomized Controlled Trials as Topic

The expression meglitinide analogs was introduced in 1995 to cover new molecules proposed as non-sulfonylurea insulinotropic agents and displaying structural analogy with meglitinide, such as repaglinide, nateglinide, and mitiglinide. Meglitinide analogs display, as judged by conformation analysis, a U-shaped configuration similar to that of antihyperglycemic sulfonylureas such as glibenclamide (glyburide) and glimepiride. In rat pancreatic islets incubated in the presence of 7.0 mmol/L D-glucose, repaglinide and mitiglinide demonstrate comparable concentration-response relationships for stimulation of insulin release, with a threshold value < 10 nmol/L and a maximal secretory response at about 10 nmol/L. Several findings indicate that meglitinide analogs provoke the closing of adenosine triphosphate-sensitive potassium channels, with subsequent gating of voltage-sensitive calcium channels. The effects of meglitinide analogs upon the binding of [3H]glibenclamide to islet cells membranes reinforces this concept. At variance, however, with other meglitinide analogs, the ionic and secretory response to repaglinide (10 micromol/L) is not rapidly reversible in perifused rat islets. In experiments conducted in vivo in control and diabetic rats, repaglinide provokes a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than glibenclamide or glimepiride. Onset of effect is also more rapid and duration of effect shorter with nateglinide versus glibenclamide. In clinical studies, single or repeated daily administration of repaglinide increased plasma insulin concentration in a dose-dependent manner, with an incremental peak reached about 2 hours after repaglinide intake. Plasma concentrations of repaglinide are about 5.0 microg/L 2-2.5 hours after oral intake of the drug. Despite the slow reversibility of repaglinide action in vitro, this drug offers advantages over glibenclamide in terms of the possible occurrence of hypoglycemia if a meal is missed. In volunteers receiving a single oral dose of nateglinide (120mg) 10 minutes before a standardized 800 Kcal breakfast, the plasma insulin concentration was higher 5, 10, and 20 minutes after meal intake than when they received a single dose of repaglinide (0.5 or 2.0mg) or placebo 10 minutes before breakfast. Peak plasma concentrations of nateglinide were reached within 2 hours in most volunteers. Peak plasma concentrations of mitiglinide were reached 30 minutes after a sing

Topics: Animals; Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines

The loss of early-phase insulin secretion is an important and early event in the natural history of type 2 diabetes. Because a normal pattern of insulin secretion is essential for the effective control of postprandial metabolism, a rational basis for the development of agents that target early-phase insulin release exists. Conventional oral hypoglycaemic agents do not target, or adequately control, postprandial glycaemia. The emergence of new classes of oral agent with a more specific mode of action provides, for the first time, an opportunity to restore early-phase insulin release. One such drug class is the meglitinide analogues (repaglinide, nateglinide, and mitiglinide). These drugs are ideally suited for combination use with metformin. They could also prove effective in combination with a thiazolidinedione, a drug class that targets insulin resistance. Exogenous insulin is frequently required in the late management of type 2 diabetes. However, one hope for newer combinations of diabetic drugs is that the functional life of the beta cell can be extended, thereby delaying the need for insulin injections.

Topics: Adult; Animals; Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine; Piperidines; Rats

Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic beta-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macrovascular disease. Therefore one of the main aims of treatment is to minimise blood glucose oscillations and attain near-normal glycosylated haemoglobin levels. Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the beta-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals. The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e.g. nephropathy with creatinine clearance < or = 50 ml/min). Meglitinide analogues act synergistically with metformin and thiazolidinediones (pioglitazone and rosiglitazone) and can be also combined with long-acting insulin (NPH insulin at bedtime). Therefore, these drugs enrich the palette of antidiabetic drugs and make the treatment more flexible and better tolerated, which both add to better metabolic control and support the empowerment and compliance of the patient. However, this will only be the

Topics: Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Molecular Structure; Nateglinide; Phenylalanine; Piperidines

Meglitinides are a group of oral hypoglycemic medications currently approved for the treatment of type 2 diabetes mellitus (T2DM). Two meglitinide molecules, Repaglinide and Nateglinide, are presently in use. Repaglinide is preferred because of its superior glycemic efficacy. They have modest efficacy with a mean decrement of glycosylated haemoglobin (HbA1c) ranging between -0.2 to -1.50% with individual therapy. Additional HbA1c reduction can occur with combination therapy with other oral hypoglycemics. This class of drugs is effective in controlling postprandial hyperglycemia with minimal risk of hypoglycemia. It is also useful in patients with variable meal timings, especially in the elderly, and in patients with renal failure. There are a dearth of long-term studies on meglitinides to assess cardiovascular outcomes or mortality in T2DM, although the Nateglinide and Valsartan in Impaired Glucose ToleranceOutcomes Research (NAVIGATOR) study showed no difference between Nateglinide and placebo with regard to the core composite cardiovascular outcomes. Based on a PubMed literature search using key words: 'meglitinides', 'repaglinide', 'nateglinide', 'HbA1c', 'glycated haemoglobin', 'cardiovascular safety', 'cardiovascular events', 'cardiovascular outcome trials', 'type 2 diabetes mellitus' and heart failure, and combining the search terms using Boolean operators 'AND', 'OR' and 'NOT' as needed we compiled current evidence for use of these oral hypoglycemic agents in clinical use. This article is an attempt to review the efficacy and cardiovascular (CV) safety of Meglitinides to help clinicians to use this class of oral hypoglycaemic agents prudently.

Topics: Aged; Benzamides; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide

To assess the association of metformin monotherapy with the risk of all-cause deaths and cardiovascular deaths and events in type 2 diabetes patients in real clinical practice.. This retrospective, observational study comprised patients with type 2 diabetes initially treated with metformin or nonmetformin monotherapy over 2011-2016. Data were extracted from the National Healthcare Big Data database in Fuzhou, China. Propensity score matching (PSM) was performed, matching each patient on metformin to one on nonmetformin in terms of a set of covariates. The primary endpoint was all-cause death, and secondary endpoints were cardiovascular death, heart failure, and heart failure hospitalization. Covariate-adjusted associations of metformin use with all the endpoints were assessed by Cox proportional hazards models.. Among 24,099 patients, 5491 were initially treated with metformin and 18,608 with nonmetformin. PSM yielded 5482 patients in each cohort. During a median follow-up of 2.02 years, we observed 110 and 211 deaths in the metformin and nonmetformin groups, respectively. Metformin was significantly associated with reduced risk of all-cause death (adjusted hazard ratio (aHR) 0.52, 95% confidence interval (CI) 0.39-0.69), cardiovascular death (aHR 0.63, 95% CI 0.43-0.91), and heart failure (aHR 0.61, 95% CI 0.52-0.73), whereas the reduced risk in heart failure hospitalization was not statistically significant (aHR 0.70, 95% CI 0.47-1.02).. In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications.

Topics: Aged; Benzamides; Carbamates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycoside Hydrolase Inhibitors; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Mortality; Nateglinide; Piperidines; Proportional Hazards Models; Retrospective Studies; Sulfonylurea Compounds; Thiazolidinediones

A new group of hybrid nitric oxide-releasing type II antidiabetic drugs possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (13 and 18), 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (14 and 19), or nitrooxyethyl (15 and 20) moiety attached to the carboxylic acid group of the type II antidiabetic drugs nateglinide and meglitinide were synthesized. These prodrugs, based on the beneficial properties of nitric oxide (NO), were designed to reduce the risk of adverse cardiovascular events in diabetic patients. Ester prodrugs (13-15 and 18-20) exhibited appreciable oral antihyperglycemic activity comparable to the parent drugs in nonfasted diabetic rats. Systolic and diastolic blood pressure profiles validated the beneficial hypotensive properties of these prodrugs. These prodrugs released NO (1.3-72.2% range) upon incubation with either phosphate buffer solution at pH 7.4 or in the presence of serum. This new type of hybrid NO donor prodrug represents an attractive approach for the rational design of type II antidiabetic drugs with a reduced risk of contraindicated cardiovascular events.

Topics: Benzamides; Blood Pressure; Cyclohexanes; Humans; Hypoglycemic Agents; Magnetic Resonance Spectroscopy; Nateglinide; Nitric Oxide; Phenylalanine; Prodrugs; Spectrometry, Mass, Electrospray Ionization

Topics: Benzamides; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine

1. The effect of N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) on nutrient metabolism was investigated in isolated rat pancreatic islets. 2. At a 10-microM concentration, the meglitinide analogue caused a modest increase in 14CO2 output from islets prelabeled with L-[U-14C]glutamine but failed to affect D-[5-3H]glucose utilization, D-[U-14C]glucose oxidation and conversion into 14C-labeled acidic metabolites and amino acids, L[1-14C]leucine and L-[U-14C]leucine oxidation, the generation of 2-ketoisocaproate and further acidic metabolites from the branched-chain amino acid and the production of 14CO2 by islets prelabeled with [U-14C]palmitate. 3. These findings indicate that the insulinotropic action of A-4166 is not attributable to any sizeable increase in the metabolism of exogenous or endogenous nutrients.

Topics: Animals; Benzamides; Cyclohexanes; Female; Glucose; Hypoglycemic Agents; Islets of Langerhans; Leucine; Nateglinide; Oxidation-Reduction; Phenylalanine; Rats; Rats, Wistar

The dynamics of the cationic and secretory response to A-4166, a hypoglycemic meglitinide analogue, was investigated in rat islets prelabelled with either 36Rb or 45Ca and placed in a perifusion system. In the absence of D-glucose, A-4166 (10 microM) provoked an immediate, sustained and rapidly reversible inhibition of 36Rb outflow, this contrasting with a short-lived stimulation of insulin release. In the presence of 6 mM D-glucose, A-4166 provoked a rapid, sustained and rapidly reversible stimulation of both insulin release and 45Ca efflux. The latter cationic response was suppressed in the absence of extracellular Ca2+, in which case A-4166 even caused a modest decrease in effluent radioactivity. These findings support the view that A-4166 acts mainly in the islet B-cell by closing ATP-responsive K+ channels, leading to subsequent depolarization of the plasma membrane and gating of voltage-sensitive Ca2+ channels. Independently of the latter effect, A-4166 may also affect the intracellular distribution of Ca2+ ions. The present data further indicate that A-4166 belongs to those hypoglycemic agents that cause rapidly reversible changes in cationic and secretory events, at variance with highly potent sulfonylureas such as glibenclamide or glimepiride.

Topics: Animals; Benzamides; Calcium; Cyclohexanes; Female; Glucose; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Pancreas; Phenylalanine; Rats; Rats, Wistar; Rubidium; Time Factors

Several meglitinide analogs are currently under investigation as potential insulinotropic tools for the treatment of noninsulin-dependent diabetes. The present study aimed to further insight into the effect of these agents on the secretion of insulin, glucagon, and somatostatin by the isolated perfused pancreas. Both repaglinide (0.01 microM) and A-4166 (1.0 microM) stimulated insulin and somatostatin release, but failed to affect glucagon output, from pancreases exposed to 5.6 mM D-glucose. The secretory response of the B- and D-cells to the hypoglycemic agents was much less marked than that caused by a rise in hexose concentration from 5.6-16.7 mM. Although repaglinide was tested at a concentration a hundred times lower than that of A-4166, the drug-induced increase in both insulin and somatostatin secretion persisted for a longer time after exposure to repaglinide, than to A-4166. The relevance of these findings to the use of meglitinide analogs as antidiabetic agents is double. First, they document that these drugs, although enhancing both insulin and somatostatin release, do not provoke an undesirable stimulation of glucagon secretion. Second, they indicate that even at a very low concentration, repaglinide provokes a protracted insulinotropic action, thus suggesting that the reversibility of the secretory response to this or other meglitinide analogs represents an intrinsic molecular attribute, unrelated to either their biological potency or the relative extent of B-cell stimulation.

Topics: Animals; Benzamides; Blood Glucose; Carbamates; Cyclohexanes; Female; Glucagon; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Nateglinide; Perfusion; Phenylalanine; Piperidines; Rats; Rats, Wistar; Somatostatin

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

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