N-(Cyclohexylcarbonyl)-D-phenylalanines and related compounds. A new class of oral hypoglycemic agents. 2

Shinkai, Hisashi; Nishikawa, Masahiko; Sato, Yusuke; Toi, Koji; Kumashiro, Izumi; Seto, Yoshiko; Fukuma, Mariko; Dan, Katsuaki; Toyoshima, Shigeshi

doi:10.1021/jm00127a006

Cited by 78 publications

(53 citation statements)

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“…1). Although nateglinide stimulates insulin secretion, it has a different chemical structure from sulfonylureas, 1,3) demonstrates a quick action/short duration type effect, 1,2,4) and its effect is believed to effectively control primarily PBG. Since blood glucose level inhibitory effects dissipate in a short period of time, nateglinide is expected to realize (1) avoidance of a hypoglycemic state, and (2) avoidance of b cell exhaustion following long-term administration and avoidance of secondary failure.…”

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confidence: 99%

Effect of Decrease in Both Postprandial Blood Glucose (PBG) and Fasting Blood Glucose (FBG) Levels in Normal Beagle Dogs with Nateglinide Enteric Coated Granules and Immediate Release Tablets

Makino

Ninomiya

Sakai

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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Ordinary antidiabetics for oral administration are classified into two types. The first type primarily controls postprandial blood glucose level (PBG), while the other type primarily controls fasting blood glucose level (FBG). 1,2) There is currently no oral antidiabetic capable of controlling both PBG and FBG, and such an antidiabetic is believed to be the most useful for the treatment of diabetes.The D-phenylalanine derivative, nateglinide ((Ϫ)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine) was developed by Ajinomoto for use as an antidiabetic (Fig. 1). Although nateglinide stimulates insulin secretion, it has a different chemical structure from sulfonylureas, 1,3) demonstrates a quick action/short duration type effect, 1,2,4) and its effect is believed to effectively control primarily PBG. Since blood glucose level inhibitory effects dissipate in a short period of time, nateglinide is expected to realize (1) avoidance of a hypoglycemic state, and (2) avoidance of b cell exhaustion following long-term administration and avoidance of secondary failure.1) Nateglinide immediate release (IR) tablets are currently available commercially in the form of Fastic ® tablets, and are used primarily for patients with mild diabetes. On the other hand, it is important to control FBG in patients with moderate and severe diabetes who exhibit elevated FBG levels. If the nateglinide oral controlled release formulation were available that is capable of controlling both PBG and FBG, it could be expected to offer the advantages of (1) improving compliance by reducing the number of administrations per day (Fastic ® tablets: 3 times per day), and (2) increasing the number of choices available for treating diabetes in moderate and severe diabetes patients.Gliclazide is an antidiabetic that is a long acting type stimulator of insulin secretion having a sulfonylurea moiety. In the case of repeated administration of gliclazide to normal rats, the blood glucose lowering action has been reported to weaken during the second administration. 5) Nateglinide is also an insulin secretion stimulator. Consequently, in the case of designing a controlled release formulation that contains nateglinide for the purpose of effectively inhibiting both PBG and FBG, there have been concerns that even if it is Nateglinide is a new quick action/short duration (QRSD) type of oral blood glucose regulator, and nateglinide immediate release tablets are used for patients with mild diabetes under the trade name of Fastic ® tablets. In this study, we attempted to determine if it was possible to control both post-prandial blood glucose level (PBG) and fasting blood glucose level (FBG) for moderate or severe diabetes through controlled release of nateglinide. Enteric coated granules were selected for the administration form for controlled release of nateglinide, and three types of enteric coated granules were prepared having dissolution pH values of 5.5, 6.5 and 7.2. The three types of enteric coated granules were each administered separately or the enteric...

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confidence: 99%

Effect of Decrease in Both Postprandial Blood Glucose (PBG) and Fasting Blood Glucose (FBG) Levels in Normal Beagle Dogs with Nateglinide Enteric Coated Granules and Immediate Release Tablets

Makino

Ninomiya

Sakai

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Nateglinide is a derivative of the amino acid D-phenylalanine (5,6), which is chemically and pharmacologically unique among oral antidiabetic agents. It acts directly on the pancreatic ␤-cells to stimulate insulin secretion that is rapid, of short duration, and dependent on ambient glucose levels (7,8).…”

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confidence: 99%

Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes.

et al. 2000

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OBJECTIVE -To evaluate the efficacy and tolerability of nateglinide and metformin alone and in combination in type 2 diabetic patients inadequately controlled by diet, focusing on changes in HbA 1c , fasting plasma glucose (FPG), and mealtime glucose excursions.RESEARCH DESIGN AND METHODS -In this randomized double-blind study, patients with an HbA 1c level between 6.8 and 11.0% during a 4-week placebo run-in received 24 weeks' treatment with 120 mg nateglinide before meals (n = 179), 500 mg metformin three times a day (n = 178), combination therapy (n = 172), or placebo (n = 172). HbA 1c and FPG were evaluated regularly, and plasma glucose levels were determined after Sustacal challenge at weeks 0, 12, and 24. Hypoglycemia and other adverse events were recorded.RESULTS -At study end point, HbA 1c was reduced from baseline with nateglinide and metformin but was increased with placebo (Ϫ0.5, Ϫ0.8, and ϩ0.5%, respectively; P Յ 0.0001). Changes in FPG followed the same pattern (Ϫ0.7, Ϫ1.6, and ϩ0.4 mmol/l; P Յ 0.0001). Combination therapy was additive (HbA 1c Ϫ1.4% and FPG Ϫ2.4 mmol/l; P Յ 0.01 vs. monotherapy). After Sustacal challenge, there was a greater reduction in mealtime glucose with nateglinide monotherapy compared with metformin monotherapy or placebo (adjusted area under the curve [AUC] 0-130min Ϫ2.1, Ϫ1.1, and Ϫ0.6 mmol и h Ϫ1 и l Ϫ1 ; P Յ 0.0001). An even greater effect was observed with combination therapy (AUC 0-130min Ϫ2.5 mmol и h Ϫ1 и l Ϫ1 ; P Յ 0.0001 vs. metformin and placebo). All regimens were well tolerated.CONCLUSIONS -Nateglinide and metformin monotherapy each improved overall glycemic control but by different mechanisms. Nateglinide decreased mealtime glucose excursions, whereas metformin primarily affected FPG. In combination, nateglinide and metformin had complementary effects, improving HbA 1c , FPG, and postprandial hyperglycemia.

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“…Nateglinide, N-[(trans-4-isopropylcyclohexyl)carbonyl]-D-phenylalanine, is the structurally optimal compound of a class of N-benzoyl-D-phenylalanines, discovered through a screen of amino acid derivatives in a search for rapid and short acting antidiabetic agents [14,15]. The R-but not the S-enantiomer was found to be active in stimulating insulin release, and the carboxyl and the phenylmethyl moieties are essential for glucose-lowering activity.…”

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confidence: 99%

The mechanisms underlying the unique pharmacodynamics of nateglinide

Boettcher

Dunning

2003

Diabetologia

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Nateglinide, a D-phenylalanine derivative, belongs to a new group of insulinotropic agents with rapid onset and short duration of action. These agents have been developed to reduce the risk of hypoglycaemia associated with pharmacological control and to decrease the likelihood of pancreatic beta-cell exhaustion. Nateglinide mediates the release of insulin from beta-cells by binding to the sulphonylurea receptors, which leads to the closure of ATP-sensitive K + channels. Increasing evidence from receptor binding, mechanistic and in vitro and in vivo insulin studies indicate unique pharmacodynamic and pharmacokinetic properties with nateglinide that are distinct from those of sulphonylureas. The time required by nateglinide to close beta-cell K ATP channels is comparable to that of glyburide but threefold and fivefold faster than repaglinide and glimepiride, respectively. Furthermore, its effects are rapidly reversed with an off-rate at the K ATP channel twice as fast as that of glyburide and glimepiride and five times faster than repaglinide. This results in a rapid and short insulin response characteristic of the physiological pattern of post-mealtime insulin release. Internalisation into beta-cells is not required for the action of nateglinide. Given that the kinetic profile of the agent is associated with selective enhancement of early-phase insulin secretion, nateglinide is expected to minimise post-meal hyperglycaemia with minimal propensity for hypoglycaemia. [Diabetologia (2003)

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N-(Cyclohexylcarbonyl)-D-phenylalanines and related compounds. A new class of oral hypoglycemic agents. 2

Cited by 78 publications

References 0 publications

Effect of Decrease in Both Postprandial Blood Glucose (PBG) and Fasting Blood Glucose (FBG) Levels in Normal Beagle Dogs with Nateglinide Enteric Coated Granules and Immediate Release Tablets

Effect of Decrease in Both Postprandial Blood Glucose (PBG) and Fasting Blood Glucose (FBG) Levels in Normal Beagle Dogs with Nateglinide Enteric Coated Granules and Immediate Release Tablets

Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes.

The mechanisms underlying the unique pharmacodynamics of nateglinide

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