Oral Antidiabetic Drugs : Ullmann's Encyclopedia of Industrial Chemistry : Wiley InterScience

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Hilmar Bischoff1 Print this page
1Bayer HealthCare AG, Wuppertal, Germany
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Copyright © 2006 by Wiley-VCH Verlag GmbH & Co. KGaA. All rights
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DOI: 10.1002/14356007.a03_001.pub2 Advanced Product Search
Article Online Posting Date: December 15, 2006 Search All Content
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Abstract
The article contains sections titled:

1. Introduction
2. Stimulators of Insulin Secretion
2.1. Sulfonylureas and Related Compounds
2.2. Benzoic Acid Derivatives
2.3. Amino Acid Derivatives
2.4. Mode of Action
2.5. New Insulinotropic Mechanisms
2.5.1. Dipeptidyl Peptidase IV Inhibition
2.5.2. Dipeptidyl Peptidase IV Inhibitors in Clinical Development
3. Biguanides
4. Inhibitors of Intestinal Carbohydrate Digestion
4.1. -Glucosidase Inhibitors
4.1.1. Mode of Action
4.1.2. Pharmacology
4.1.3. Individual Compounds
4.2. Plant Fibers
5. Enhancers of Insulin Action
5.1. Mode of Action
5.2. Pharmacology of PPAR agonists
5.3. Thiazolidine-2,4-Dione Derivatives (Glitazones)

The review describes all oral drugs used for the treatment of type 2 diabetes mellitus which are marketed or in late clinical
development. Stimulators of insulin secretion are the most prescribed class of antidiabetic drugs. These compounds increase
insulin secretion from pancreatic -cells via the closure of the ATP-sensitive K+ channel. Sulfonylurea (SU) derivatives bind
to the SU receptor on a regulatory protein of the ATP-sensitive K+ channel. Since various binding sites exist, also other
compounds like benzoic acid or amino acid derivatives are able to bind and to stimulate insulin secretion via the closure of
the ATP-sensitive K+ channel. Very new mechanisms, not yet approved and still in late clinical development, prevent the
degradation of glucagons-like-peptide-1 (GLP-1), an intestinal hormone, which stimulates insulin secretion by increasing
intracellular cAMP levels of -cells. Those compounds, which inhibit the GLP-1 degrading enzyme dipeptidyl peptidase IV
(DPP IV), sustain the insulinotropic effect of GLP-1. The antidiabetic action of biguanides, only metformin is marketed today,
is still not fully understood. Metformin improves insulin sensitivity probably by an increase in peripheral glucose utilization and
additionally metformin reduces hepatic gluconeogenesis. Alpha-glucosidase inhibitors are enzyme inhibitors of small
intestinal carbohydrate digesting glucosidases. They display their antidiabetic effect by delaying the postprandial (pp)
carbohydrate absorption resulting in reduced pp hyperglycemia and -insulinemia, which finally improves insulin sensitivity.
Enhancers of insulin action are ligands of the peroxisome proliferator activated receptor (PPAR ). PPARs belong to the
nuclear receptor family of ligand-activated transcription factors. The major antidiabetic and blood glucose lowering effect of
the PPAR agonists is the improvement of insulin sensitivity, however, the mechanism is not fully elucidated yet.

[Top of Page]

1. Introduction

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Oral Antidiabetic Drugs : Ullmann's Encyclopedia of Industrial Chemistry : Wiley InterScience
Type 2 diabetes or noninsulin dependent diabetes mellitus (NIDDM) is a chronic disease of impaired carbohydrate, lipid, and
protein metabolism, resulting from inadequate insulin action. Patients may have diminished insulin secretion, i.e., insulin
deficiency, or insulin is secreted but does not act properly because of impaired sensitivity of muscle and liver to insulin
(insulin resistance) [1], [2]. The treatment with antidiabetic drugs is aimed at achieving glycemic control to prevent the
development of diabetic complications: neuropathy, nephropathy, and retinopathy. Oral antidiabetic drugs reduce or
normalize elevated concentrations of glucose in blood and urine. Antidiabetic drugs available today aim at various target
tissues and can be characterized by their different mode of actions. Basically two major pharmacological principles can be
distinguished: (1) stimulation of insulin secretion (A) and (2) mechanisms where no elevated plasma insulin levels are
required for glycemic control (B – D):

A. Insulin secretagogues act on the -cells of the pancreas and stimulate insulin secretion.
B. Biguanides affect the glucose metabolism in the liver and peripheral tissues (e.g., skeletal muscle).
C. Inhibitors of carbohydrate digestion are active in the small intestine and delay carbohydrate digestion and glucose
absorption.
D. Insulin sensitizers primarily act on peripheral tissues and enhance insulin action.

[Top of Page]

2. Stimulators of Insulin Secretion

2.1. Sulfonylureas and Related Compounds
When testing sulfonamide derivatives for antibacterial activity LOUBATIERES recognized their blood glucose lowering potential
already in 1944 [3]. However, it took more than 10 years before the first non-antibacterial compounds carbutamide
(Boehringer Mannheim) [4] and tolbutamide (Hoechst) [5] (Table 1) were introduced into the market for the treatment of type
2 diabetic patients in 1956.

Sulfonylurea (SU) derivatives of the first generation were active only in high dosages of up to 2000 mg/d. Sulfonylureas of the
“second generation” showed much higher pharmacological potency and were active in significantly lower doses [6]. The first
one, glibenclamide (glyburide) (Table 1), was introduced in the market by Boehringer Mannheim and Hoechst in 1969
requiring daily doses of only 2.5 – 15 mg.

Although the efforts in pharmaceutical sulfonylurea research decreased in the 1970s, investigations in the last two decades
have been concentrated on increasing, prolonging, or shortening the action of insulin secretagogues or accelerating their
onset of action. Glimepiride (Table 1), a structure closely related to glibenclamide in which the phenyl substituent of
glibenclamide is replaced by pyrroline, was introduced into the market in 1996. In contrast to glibenclamide, in several animal
species glimepiride is characterized by a faster onset of blood glucose lowering activity, and a longer-lasting glucose
lowering effect [7].

Also in clinical trials, glimepiride showed longer-lasting hypoglycemic effects than glibenclamide [8]. Due to these properties,
glimepiride was introduced as a drug for once-daily treatment. Although all 14 SU compounds of Table 1 are available at
least in parts of the world, more than 90 % of the SU world market is dominated by only five SU derivatives —
glibenclamide/glyburide, gliclazide, glipizide, chlorpropamide, and glimepiride (Table 1).

Table 1. Examples of insulin secretion simulators (daily dose for humans and threshold dose for rabbits) and
elimination half life 1/2

Generic name Examples of commercial preparations Daily Threshold 1/2

dose, dose,
Mr, mp, Ref. formula mg mg h

Sulfonylureas

Acetohexamide [ Dimelor (Lilly) 250 – 10 4–7

968-81-0] 500
C15H20N2O4S
324.2, 188 – 190 °
C,

[9]
N-(4-Acetylbenzenesulfonyl)-N′-cyclohexylurea
Carbutamide [ Nadisan (Boehringer Mannheim) Invenol 500 – 200 40

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Oral Antidiabetic Drugs : Ullmann's Encyclopedia of Industrial Chemistry : Wiley InterScience
339-43-5] (Hoechst) 2000
C11H17N3O3S
271.3, 140 – 143 °
C,

[10], [11]
N-Sulfanilyl-N′-n-butylurea
Chlorpropamide [ Chloronase (Hoechst) Diabetoral 125 – 10 35
94-20-2] (Boehringer Mannheim) Diabenese (Pfizer) 500
C10H13ClN2O3S
276.6, 126 – 128 °
C,

[5]
N-(4-Chlorobenzenesulfonyl)-N′-n-propylurea
Glibornuride [ Gluborid (Grünenthal) Glutril (Hoffmann-La 12.5 – 1 5–7
26944-48-9] Roche) 75
C18H26N2O4S
366.4, 192 – 195 °
C,

[12]
N-(Tosyl)-N′-(2-endo-hydroxy-3-endo-DL-bornyl)-urea
Glyburide Euglucon (Boehringer Mannheim, Hoechst) 1.75 – 0.01 5–8
(Glibenclamide) [ Daonil (Hoechst) 20
10238-21-8]
C23H28ClN3O5S
495.0, 172 – 174 °
C,

[6]
N-4-[2-(Chloro-2-methoxybenzamido)-ethyl]-benzenesulfonyl)-N′-cyclohexylurea
Gliclazide [ Diamicron (Science Union, Servier) 40 – 240 1.0 7
21187-98-4]
C15H21N3O3S
323.2, 180 – 182 °
C,

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Oral Antidiabetic Drugs : Ullmann's Encyclopedia of Industrial Chemistry : Wiley InterScience

[13]
N-(Tosyl)-N′-(3-aza-bicyclo-[3.3.0.]-3-octyl)-urea
Glimepiride [ Amaryl (Hoechst/Sanofi-Aventis) 1–6 1.5 –
93479-97-1] 3.5
C24H34N4O5S
490.62, 207 °C,

[14]
Trans-3-ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(4-methylcyclohexyl) amino]carbonyl]amino]sulfonyl]
phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide
Glipizide [ Glibenese (Pfizer) Mini Diab (Carlo Erba) 2.5 – 20 0.02 2–4
29094-61-9]
C21H27N5O4S
445.5, 208 – 209 °
C,

[15]
N-{4-[5-methylpyrazine-2-carboxamido)-ethyl]-benzenesulfonyl}-N′-cyclohexylurea
Gliquidone [ Glurenorm (Thomae) 15.0 – 2.5 2–4
33342-05-1] 120
C27H33N3O6S
527.3, 180 – 182 °
C,

[16]
N-{4-[2-(3,4-Dihydro-7-methoxy-4,4-dimethyl-1,3-dioxa-2(1H)-isoquinolyl)-ethyl]-benzenesulfonyl}-
N-cyclohexylurea
Glisoxepide [ Pro-Diaban (Bayer, Schering) 2.0 – 16 0.05 2–4
25046-79-1]

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Oral Antidiabetic Drugs : Ullmann's Encyclopedia of Industrial Chemistry : Wiley InterScience
C20H27N5O5S
449.5, 194 – 198 °
C,

[17], [18]
4-{4-[ -(5-Methylisoxazolyl-3-carboxamido)-ethyl]-benzenesulfonyl}-1,1-
hexamethylenesemicarbazide
Glymidine Redul S (Schering) 500 – 20 4
(Glycodiazine) [ 1500
3459-20-9]
C13H14N3O4SNa
331.2, 221 – 226 °
C,

[19]
2-Benzenesulfonamido-5-(2-methoxyethoxy)-pyrimidine sodium
Tolazamide [ Norglycin (Upjohn) Tolinase (Upjohn) 125 – 5 7
1156-19-0] 1000
C14H21N3O3S
311.4, 165 – 173 °
C,

[20]
N-(Tosyl)-N′-(hexahydro-1H-azepin-1-yl)-urea
Tolbutamide [ Artosin (Boehringer Mannheim) Rastinon 500 – 10 5–7
64-77-7] (Hoechst) Orinase (Upjohn) 3000
C12H18N2O3S
270.4, 127 – 129 °
C,

[5]
N-(Tosyl)-N′-n-butylurea
Tolcyclamide Diaboral (Carlo Erba) 150 – 10 6–7
(Glyciclamide) [ 1000
664-95-9]
C14H20N2O3S

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Oral Antidiabetic Drugs : Ullmann's Encyclopedia of Industrial Chemistry : Wiley InterScience
296.4, 174 – 175 °
C,

[5]
N-(Tosyl)-N′-cyclohexylurea
Benzoic Acid Derivative
Repaglinide [ Novonorm (Novo Nordisk) 1.5 – 16 0.5 –
135062-02-1] 1
C27H36N2O4
452.59, 126 – 131 °
C,

[21]
(S)-2-Ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoic acid
Amino Acid Derivative
Nateglinide [ Starlix (Novartis) 180 – 1–2
491828-09-2] 360
C19H27NO3
317,43

[22]

2.2. Benzoic Acid Derivatives

Research on the structure-activity relationship of potent “second generation” SUs like gliblenclamide has revealed that the
nonsulfonylurea moiety of glibenclamide also stimulated insulin secretion. The benzoic acid derivative meglitinide (HB 699)
stimulated insulin release in vitro and in vivo, but the potency was only comparable to tolbutamide [8]. Repaglinide, the active
(S)-enantiomer of AG-EE 388 ZW (Boehringer Ingelheim) (Table 1) is a benzoic acid derivative with remarkably higher
potency, comparable with glibenclamide [23]. Due to its different pharmacokinetic behavior from glibenclamide, more rapid
absorption, and shorter half-life, repaglinide showed interesting pharmacological properties in terms of quick insulin release
and short-acting blood glucose lowering effects [24]. Repaglinide was introduced into the market in 1998.

2.3. Amino Acid Derivatives

Amino acid derivatives derived from D-phenylalanine are structurally a new type of insulin secretagogues [23].

Nateglinide (A-4166), Starlix, shows stereospecific activity, and it was found that the R-configuration was essential for
hypoglycemic activity.

It is suggested that the phenylmethyl substituent of the amino acid residue is essential for activity. Variation of the amino acid
moeity, e.g., glycine, alanine, phenylglycine, tyrosine, and others reduced the hypoglycemic activity [23]. Nateglinide
produces a very quick insulin release followed by a rapid onset of blood glucose decrease and shows a short duration of
action [25], [26]. Clinical trials have demonstrated mild blood glucose lowering activity after single doses of 60 – 180 mg. The
first market introduction was in 1999 in Japan and in 2001 in USA.

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Mitiglinide [145525-41-3] (KAD-1229, Kissei Pharmaceutical) is another non-sulfonylurea insulin secretagogue [27].
Mitiglinide is a benzylsuccinic acid derivative and in phase III of clinical development.

2.4. Mode of Action

Insulin secretion is physiologically stimulated by the binding of ATP to a cytosolic nucleotide binding site of the membrane
bound ATP-sensitive K+ channel which leads to closure of the K+ channel. The inhibition of K+ permeability depolarizes the
plasma membrane, subsequently the voltage-dependent Ca2+ channel opens to promote the Ca2+ influx which finally results
in insulin secretion [28].

The insulin secretagogues stimulate insulin secretion by closure of this ATP-sensitive K+ channel of pancreatic -cells. The
KATP-channel consists of two subunits, a functional ion channel pore and a regulatory protein. The binding of the
secretagogues is suggested to occur to the separate regulator protein containing the binding sites for sulfonylureas
(sulfonylurea receptor 1, SUR1) but also other compounds [26], [27], [29].

2.5. New Insulinotropic Mechanisms

In 2005, a new antidiabetic principle was approved in the USA and introduced in the market: exendin-4 (Exenatide) [30], [31],
an injectable analogue of the gastrointestinal peptide hormone glucagon-like peptide-1 (GLP-1) (see Peptide and Protein
Hormones). GLP-1 stimulates insulin secretion in a glucose-dependent manner with little risk of hypoglycemia via activation
of the -cell hormone receptor. Additionally, GLP-1 shows further important effects on -cells, insulin biosynthesis and
glucagon secretion, as well as on gastric motility. However, GLP-1 is unsuitable as a therapeutic agent, because of rapid
enzymatic degradation by dipeptidyl peptidase IV (DPP IV also known as CD26) which results in a half-life of about two
minutes [32].

2.5.1. Dipeptidyl Peptidase IV Inhibition

Very shortly after the discovery in 1993 that DPP IV inactivates GLP-1 [33], the inhibition of DPP IV was proposed as a new
antidiabetic therapy using the attractive antidiabetic profile of GLP-1 [34]. Differently from injectable peptide hormones, all
DPP IV inhibitors under development are orally available drugs.

DPP IV inhibitors sustain the plasma concentrations of GLP-1 by preventing the N-terminal degradation of GLP-1 [35], which
results in significant enhancement of its insulinotropic activity, as well as improvement of islet function, which has been
observed in long-term animal studies with DPP IV inhibitors [36], [37].

In general, good tolerability has been reported for DPP IV inhibitors in clinical studies. However, little data are available with
respect to selectivity regarding other DPPs (e.g., DPP 8/9) [38], [39] and consequences of their inhibition are unknown. And
because DPP IV cleaves and inactivates a variety of peptide hormones, special observation in long-term trials is needed for
the safety evaluation of this class of drugs.

2.5.2. Dipeptidyl Peptidase IV Inhibitors in Clinical Development

The most advanced compounds in clinical phase III trials are vildagliptin [274901-16-5] (LAF-237, Novartis) [40]

and sitagliptin [274901-16-5] (MK-0431, Merck & Co.) [41].

The only published long-term (52 weeks) trial results are available for vildagliptin (50 mg OD) in combination with metformin.
Vildagliptin showed reductions in HbA1C after 12 weeks ( = –0.7 %) and good tolerability after 52 weeks [42]. Further long-
term clinical trials with both, vildagliptin and sitagliptin, are still ongoing. Although no long-term data are published with
sitagliptin, in USA a new drug approval (NDA) for sitagliptin was filed in early 2006. It is too early for an evaluation of the

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therapeutic efficacy, but in general, one may say DPP IV inhibitors reduce glycemia and glucagon levels, sustain insulin
levels in patients, improve the glucose tolerance and as a glucose-dependent insulin secretagogue they avoid serious
hypoglycemic events [43], [44].

[Top of Page]

3. Biguanides
The hypoglycemic activity of guanidine derivatives was firstly reported in 1918 [45]. The first blood glucose lowering
diguanidine derivative decamethylenediguanidine (Synthalin A) was synthetized in the 1920s. Because of liver toxicity
development of these compounds was discontinued. Only in the 1950s three biguanides were developed. The disubstituted
dimethylbiguanide metformin [657-24-9] was introduced in 1957.

Monosubstituted compounds with a longer side chain, the phenylethylbiguanide phenformin [114-86-3] and the N-
butylbiguanide buformin [692-13-7], were introduced in the same year and 1958, respectively [46].

Pharmacology and Mode of Action. Biguanides are ineffective in normal animals, unless very high doses are used and
there is no risk of hypoglycemia. However, in diabetic animals blood glucose-lowering effects of biguanide can be
demonstrated, depending on the model used. Biguanides do not stimulate insulin secretion, but need insulin for
pharmacological hypoglycemic activity. In severe insulinopenic animal models, high doses have to be used and effects are
modest. In mild diabetic animals or in insulin resistant animals, lower doses are already efficacious in lowering hyperglycemia
and hyperinsulinemia [47].

The mechanism of action of biguanides is still not fully understood. Three major tissues have been identified as
pharmacological sites of action: (1) the small intestinal wall, (2) the liver, and (3) peripheral tissues, mainly the skeletal
muscle:

1. For the small intestine an inhibition of glucose absorption was described, however, this is, at least for metformin, of
minor significance and not important for the blood glucose lowering effect. However, the intestinal glucose
metabolization to lactate is stimulated and reduces the postprandial uptake of glucose by the liver.
2. Numerous studies have shown that biguanides inhibit hepatic gluconeogenesis and this may contribute to the blood
glucose lowering effect, particularly in the fasting state. Again, metformin has probably less impact on
gluconeogenesis than phenformin and buformin.
3. In the peripheral tissues, metformin increases the glucose disposal and utilization particularly in the skeletal muscle,
which is probably the major contribution to the blood glucose lowering activity. In vitro studies using cell cultures have
shown that metformin potentiates insulin action. In vivo studies in animals and diabetic patients have demonstrated
that metformin reduces insulin resistance, at least in obese individuals [47], [48].
Phenformin and buformin may cause lactic acidosis, which is the most serious adverse event of biguanides. Due to
very serious cases of lactic acidosis both drugs were withdrawn from the markets in most parts of the world during the
1970s. Today they are available only in a few countries of Eastern Europe and South America. Owing to a more
favorable pharmacokinetic profile of metformin, metformin associated lactic acidosis is very rare [48]. Therefore, only
metformin is available today in all important countries. In the 1990s metformin experienced a renaissance in many
countries, particularly in the USA, where metformin was approved for the treatment of type 2 diabetes only in 1994.

[Top of Page]

4. Inhibitors of Intestinal Carbohydrate Digestion

Delaying absorption as a therapeutic principle is well accepted for dietary therapy to avoid high postprandial blood glucose
excursions [49]. Carbohydrates represent quantitatively the major portion of the human diet, in the form of mono-, di- and
polysaccharides. However, only the relatively infrequently occurring monosaccharides such as glucose and fructose can be
absorbed and are readily taken up from the small intestine. The more important dietary carbohydrate components, the
complex starches and also sucrose have to be hydrolyzed enzymatically to their constituting monosaccharides by specific
intestinal -glucosidases ( -amylase, glucoamylase, dextrinase, maltase, isomaltase and sucrase) before they can be
absorbed. The high density of intestinal membrane bound -glucosidase enzymes in the jejunum and the high proportion of
refined carbohydrates in the Western diet are the main reasons that the digestive process usually takes place very rapidly in
the proximal small intestine. As a result, a high carbohydrate digestion rate leads to a rapid postprandial rise in blood glucose
which is followed by a glucose stimulated insulin increase [50].

4.1. -Glucosidase Inhibitors

-Glucosidase inhibitors are of various chemical structures (polypeptides and carbohydrates). The most potent inhibitors are
from a carbohydrate-derived backbone containing a nitrogen atom in the molecule. Polypeptides are less active.

4.1.1. Mode of Action

Essential for the action of the carbohydrate-type -glucosidase inhibitors is their intramolecular nitrogen atom, which binds to
the carbohydrate binding site of the intestinal -glucosidases [51]. Compared with the oxygen atom of the -glycosidic bond
of dietary complex carbohydrates, the affinity of the nitrogen atom to the carbohydrate binding site of the enzyme is much

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higher (factor 104 – 107). Despite their high affinity for these enzymes, the binding of -glucosidase inhibitors is reversible
and their inhibition kinetics are competitive [52].

4.1.2. Pharmacology
Pharmacological inhibition of intestinal -glucosidases effectively retards the digestion of carbohydrates, slows down the
absorption of glucose and avoids the often very high postprandial blood glucose peaks particularly in diabetic patients. As a
result the postprandial glycemia and glucose stimulated hyperinsulinemia are flattened and the metabolic control will be
improved. From the primary pharmacological effects, it can be concluded that -glucosidase inhibitors act to reduce
postprandial hyperglycemia without stimulating insulin secretion, thus avoiding any risk of hypoglycemia. Because of their
unique mode of action in the small intestine, -glucosidase inhibitors can be used in combination with all other antidiabetic
treatments and act in an additive manner together with other antidiabetic drugs [50].

4.1.3. Individual Compounds

The first active compounds were inhibitors of the soluble pancreatic -amylase. BAY D 7791 was a protein isolated from
wheat flour [53]. This -amylase inhibitor inhibited the postprandial blood glucose rise in oral loading tests with raw starch,
but was much less effective when used together with cooked starch.

BAY E 4609, an -amylase inhibitor of microbial origin, was characterized to be of carbohydrate nature and showed a
significantly higher inhibitory potency [53]. However, also this compound demonstrated only modest efficacy in clinical trials.
Because -amylase inhibitors affect only starch digestion, the degradation of important oligo- and disaccharides by the
membrane bound enzymes is not inhibited, the overall efficacy is only modest.

Further research aimed at inhibitors of the membrane bound -glucosidases. This approach was very successful and lead to
the discovery of acarbose (Table 2) [54], the first -glucosidase inhibitor, which was introduced into the market for the
treatment of type 2 diabetic patients in 1990 (in many countries also for type 1 in addition to insulin).

Table 2. -Glucosidase inhibitors

Generic Examples of commercial preparations Daily dose

name
Mr, mp, Ref. formula

Acarbose [ Glucobay, Precose, Prandase, Glucor (Bayer) 100 – 300 mg

56180-94-0]
C25H43NO18

645.61;
amorph
[55]
O-{4,6-Dideoxy-4-[1(S)-(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyclohexene-1-yl]amino- -
D-glucopyranosyl}-(1 4)-O- -D-glucopyranosyl-(1 4)-D-glucose
Miglitol [ Diastabol (Sanofi) Glyset (Pfizer) Seibule (Sanwa Kagaku) 50 – 300 mg
72432-03-2]
C8H17NO5

207.23; 114 °

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C
[56]
1,5-Dideoxy-1,5-[(2-hydroxyethyl)imino]-D-glucitol
Voglibose [ Basen (Takeda) 0.3 – 0.9 mg
83480-29-9]
C10H21NO7

267.28; 162 –
163 °C
[57]
3,4-Dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxy-methyl)-D-epiinositol

Acarbose is a pseudotetrasaccharide of microbial origin, and was isolated from bacterial culture broths (Actinoplanes spec.)
by Bayer [51], [52]. Acarbose consists of an acarviosine unit and maltose. The acarviosine nitrogen is responsible for the
high affinity to the active binding site of -glucosidases, however, the C – N linkage cannot be hydrolyzed and the enzymatic
reaction stops.

Further research generated smaller molecules with different structures. The synthetic N-substituted valiolamine and the N-
substituted 1-deoxynojirimycin derivatives showed even higher affinity to various -glucosidases [51], [53].

The 1-deoxynojirimycin derivative miglitol (BAY M 1099) (Table 2) shows similar activity to acarbose with daily dosages of
50 – 300 mg [52].

Emiglitate (BAY O 1248) [80879-63-6], another deoxynojirimycin analogue is characterized by at least five-fold higher
inhibitory potency than acarbose and additionally shows a long-lasting inhibitory effect [51], [52].

In animal studies emiglitate was still active up to 17 h after a single oral administration due to its pharmacokinetic behavior
(formation of an active metabolite) [53], [58]. Both miglitol and emiglitate differ in their pharmacokinetic behavior from
acarbose, which is poorly absorbed (1 – 2 %). The deoxynojirimycin derivatives are structurally related to monosaccharides
and will be absorbed in the jejunum [58].

The most potent -glucosidase inhibitor is the valiolamine derivative voglibose (Takeda) (Table 2). Compared with acarbose
its inhibitory potency in vitro, depending on the -glucosidase enzyme, is up to 200 times higher [51], [53]. In Japan, daily
dosages are only 0.3 – 0.9 mg, however, therapeutic efficacy on HbA1c reduction could not be clearly demonstrated with
those dosages. HbA1c, a glycated hemoglobin species, which occurs in blood, is a diagnostic measure for the non-enzymatic
glycation process, and depends on the plasma glucose concentration. The process of protein glycation is discussed to be
responsible for the development of diabetic complications (neuropathy, retinopathy, nephropathy). In Europe voglibose is
under evaluation with distinctly higher daily dosages of 1.5 to 6 mg [59]. In contrast to acarbose, the smaller inhibitors of the
monosaccharide type (miglitol, emiglitate, voglibose) do not inhibit pancreatic -amylase [51], [53].

4.2. Plant Fibers

A more dietary approach for delaying absorption of nutrients is the use of undigestable carbohydrate polymers. Guar gum [
9000-30-0] is a galactomannan obtained from the seeds of the guar plant (Cyamopsis tetragonoloba). Guar gum has no
specific pharmacological site of action, but delays the absorption of digestible carbohydrates because it increases the
viscosity in the small intestine and additionally hinders physically the enzymatic degradation of digestible carbohydrates. This
approach is less effective in delaying the carbohydrate absorption than the pharmacological approach by the use of -
glucosidase inhibitors.

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5. Enhancers of Insulin Action

The thiazolidine-2,4-dione derivatives (TZDs or glitazones) are insulin sensitizing compounds which improve glucose
utilization without stimulating pancreatic insulin secretion. However, the thiazolidinediones are only active in conjunction with

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insulin and show the best results in hyperinsulinemic, insulin resistant, obese individuals (animals and humans). The first
compound ciglitazone, synthetized by Takeda and reported in 1982, was a result of screening of clofibrate analogues for
hypolipidemic activity [60], [61].

5.1. Mode of Action

The mechanism of blood glucose lowering activity by thiazolidinedione derivatives has not been fully elucidated yet. Only
minor or no effects are observed in normal animals or insulin sensitive diabetes models. In obese or hyperinsulinemic insulin
resistant rodents thiazolidinediones lower insulin and triglyceride levels after treatment for 2 to 8 d. If hyperglycemia occurs,
also the blood glucose concentration is reduced [23], [61].

Mechanistic in vitro studies with adipocytes have shown that the thiazolidinediones are ligands of the peroxisome proliferator
activated receptor [62]. Peroxisome proliferator activated receptors (PPARs) belong to the nuclear receptor superfamily of
ligand-activated transcription factors.

So far, three receptor subtypes have been identified: PPAR , PPAR , and PPAR . The PPARs are believed to play a
physiological role in the regulation of lipid metabolism [63], [64]. The in vivo antihyperglycemic activity of thiazolidinediones
strongly correlates with their potency as PPAR agonists in vitro [65]. The mechanisms responsible for the blood glucose
effects are controversally discussed, however, as long as there are no more mechanistic data available it is suggested that
PPAR is a primary site of action of the thiazolidinediones [66].

5.2. Pharmacology of PPAR agonists

Ciglitazone reduced plasma triglycerides, hyperglycemia and hyperinsulinemia in several insulin resistant diabetic and non-
diabetic rodent models after repeated oral dosing at doses of 100 – 300 mg/kg body weight, while having little or no effect in
normal rodents or those with insulin deficient diabetes [61]. In long-term animal studies lens cataracts occurred and
ciglitazone development was discontinued. Further synthetic research on thiazolidinedione analogues yielded compounds of
distinctly higher in vitro and in vivo activity. Depending on the animal model, after repeated dosing troglitazone lowered
hyperglycemia as well as levels of free fatty acids, triglycerides, and insulin at daily doses of 50 mg/kg p.o. or slightly lower
[23], [67]. The glitazones are not only able to reduce insulin resistance, in vitro and in vivo studies have demonstrated
increased synthesis of glucose transporter 1 (GLUT1) in various tissues. Little or no effect was observed on the insulin
sensitive glucose transporter 4 (GLUT4), synthesis or insulin stimulated translocation of GLUT4, particularly in adipocytes,
were only slightly increased. These effects may contribute to increased cellular glucose uptake [68].

In accordance with the PPAR mechanism, which primarily affects the adipose tissue, all obese animals gain weight under
treatment with glitazones [64].

5.3. Thiazolidine-2,4-Dione Derivatives (Glitazones)

Clinical trials have confirmed the preclinical results. Best effects were observed in obese, highly insulin resistant type 2
diabetic patients and particularly in combination with insulin secretagogues (SU). However, the increase in body weight gain
was also observed [64].

Troglitazone (Sankyo, see Table 3) was firstly approved 1995 in Japan and 1997 in USA and UK. It was launched in these
countries in 1997. The recommended starting dose was 400 mg/d and the highest dose 600 mg. After being marketed, the
daily practice revealed adverse events in the liver with cases of fatal liver failure. This lead to withdrawal of troglitazone from
the market in the UK already after two months [69], in USA and Japan in the year 2000 [70].

Table 3. Thiazolidine-2.4-dione derivatives (TZDs)

Generic name Examples of commercial preparations Daily dose

Mr, mp, Ref. formula

Pioglitazone [ Actos (Ely Lilly) (Takeda) 15 – 45 mg

112529-15-4]
C19H20N2O3S · HCl

392.90; 183 – 184 °C

[72]
(±)-5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, hydrochloride
Rosiglitazone [ Avandia (SKB) 4 – 8 mg
122320-73-4]
C18H19N3O3S

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357.43; 122 – 123 °C

[73]
5-(4-[2-(Methylpyridin-2-ylamino)ethoxy]benzyl)thiazolidine-2,4-dione
Troglitazone [ Noscal (Sankyo) Rezulin (Warner-Lambert) 400 – 600 mg
97322-87-7]
C24H27NO5S

441.55; 184 – 186 °C

[74]
5-[[4-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy]phenyl]methyl]-
2,4-thiazolidinedione

Pioglitazone (Table 3) is approximately ten times more potent in both, animals, and humans than troglitazone. The highest
potency shows rosiglitazone (Table 3), which is approximately 100-fold more active than troglitazone [69]. Both compounds
showed better tolerability in clinical trials than troglitazone. Both drugs were introduced into the US market in 1999, and
differently from troglitazone, for these TZDs, hepatotoxicity is less serious. However, both drugs cause fluid retention,
therefore, heart failure could be a potential risk for special patients [71].

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