Description
Nateglinide is a N-acylated D-phenylalanine marketed in
Japan as novel orally active insulinotropic agent for the treatment of type-2
diabetes mellitus. It belongs to the class of nonsulfonylureas and shows some
structural similarity to repaglinide, the only other representative in this family. In
single pancreatic beta-cells isolated from rats, Nateglinide was found to
specifically block the ATP-sensitive K+ channel resulting in an increase in
intracellular calcium concentration. This primary action would underlie the
mechanism by which Nateglinide markedly stimulates or potentiates, depending
on glucose concentrations, insulin secretion from pancreatic beta-cells. Clinical
studies demonstrated a good safety profile with a low potential for
hypoglycemia. The pharmacokinetic profile was consistent with the changes of
the blood glucose and plasma insulin level. Interestingly, Nateglinide exerts a
rapid onset and short duration of action due to a rapid absorption and clearance.
Unlike other similar agents, Nateglinide suppresses postprandial glucose
elevations.
Chemical Properties
Cyrstalline Solid
Originator
Ajinomoto (Japan)
Definition
ChEBI: An N-acyl-D-phenylalanine resulting from the formal condensation of the amino group of D-phenylalanine with the carboxy group of trans-4-isopropylcyclohexanecarboxylic acid. An orally-ad
inistered, rapidly-absorbed, short-acting insulinotropic agent, it is used for the treatment of type 2 diabetes mellitus.
Brand name
Starlix (Novartis);Fastic;Starsis.
General Description
Although nateglinide, N-(4-isopropylcyclohexanecarbonyl)-D-phenylalanine (Starlix), belongs tothe metaglinides, it is a phenylalanine derivative and representsa novel drug in the management of type 2 diabetes.
General Description
Nateglinide (Starlix) is D-Phenylalanine, N-[[trans-4-(1-methylethyl)cyclohexyl]carbonyl]-; or (-)-N-[(trans-4-isopropylcyclohexyl)carbonyl]-D-phenylalanine. Itis noteworthy that, although nateglinide is much less potenton a dosage basis than is repaglinide and most of the sulfonylureas,this drug seems to exhibit unique molecularpharmacodynamics. Nateglinide closes ATP-sensitive K channels some threefold more rapidly than repaglinide, andexhibits an off-rate twice as fast as that of glyburide orglimepiride and five times faster than repaglinide. Thesecharacteristics are reflected by the systemic pharmacodynamicsof this drug, translating clinically to improvedsafety, among other apparent benefits.
Biochem/physiol Actions
Nateglinide is a Kir6.2/SUR1 channel inhibitor and antidiabetic. It is selective for the SUR1 subtype, which is found on pancreatic islet cells. Nateglinide evokes KATP channel-dependent insulin secretion (50-200 μM) in the absence and presence of insulin.
Mechanism of action
Approved in the United States in late 2000, nateglinide is a rapidly absorbed insulin secretagogue that has a mechanism of
action similar to that of repaglinide, with effects appearing within 20 minutes following oral dosing.
Bioavailability is 73%,
and it is 98% protein bound, primarily to albumin. Nateglinide is tissue selective, with low affinity for cardiac and skeletal
muscle.
Clinical Use
Treatment of type 2 diabetes in combination with
metformin
Synthesis
The general procedure for the synthesis of (R)-2-rel-((1r,4R)-4-isopropylcyclohexanecarboxamide)-3-phenylpropanoic acid from D-phenylalanine and trans-4-isopropylcyclohexanecarboxylic acid chloride (CAS:100597-38-4) was as follows:
1. D-phenylalanine (20.02 g) was added in a single addition to a 3.5% NaOH solution (total 410.5 g, 2.99 eq.), heated to 39 °C and stirred at a rate of 150 rpm for 150 min until a clarified solution was formed.
2. trans-4-isopropylcyclohexanecarboxylic acid chloride (24.73 g) was added in a single addition to the above hot reaction mixture.
3. The reaction mixture (clarified solution) was stirred at 44-45 °C for 25 minutes.
4. Ethyl acetate (140 ml) was added to the reaction mixture on a one-time basis, followed by addition of 85% H2SO4 solution (14.08 g) and adjusting the pH to 1-2.
5. The hot organic layer was separated, washed twice with water (100 ml) at 30 °C and filtered through a PTFE 0.45 μm filter.
6. The clarified solution (141 g) was heated to 46 °C, heptane (153 ml) preheated to 46 °C was added and mixed at a stirring rate of 150 rpm.
7. The clarified solution was gradually cooled to 28°C and inoculated with δ-crystalline seeds.
8. After crystallization occurred at 24 °C, stirring was continued for 30 min, then gradually cooled to 5 °C and stirred at 5 °C overnight.
9. The solid was collected by filtration and washed with a cold (5 °C) heptane-ethyl acetate mixture (6:1, total 30 ml) to give 49.1 g of wet product (50% humidity).
10. The wet product was dried at 23 °C/20 mbar for 24 h to give 24.65 g of δ-crystalline product with >99.8% purity and 65% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin.
Antifungals: hypoglycaemic effect possibly enhanced
by fluconazole.
Lipid-lowering agents: hypoglycaemic effect possibly
enhanced by gemfibrozil.
Metabolism
It is metabolized in the liver, with 16% excreted in the urine unchanged. The major metabolites are hydroxyl
derivatives (CYP2C9, 70%; CYP3A4, 30%) that are further conjugated to the glucuronide derivatives.
References
[1] Patent: US2005/14836, 2005, A1
[2] Patent: US2005/14836, 2005, A1
[3] Patent: EP1334963, 2003, A1
