Transcript Diuretics and Synthetic Hypoglycemic Drugs

Chapter 10
Diuretics and Synthetic
Hypoglycemic Drugs
Pei Yu
College of pharmacy
Jinan University
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Synthetic Hypoglycemic Agents
(降血糖药)
Definitions
A key indicator of diabetes is persistent
fasting blood glucose levels above 11.1
mmol/L which arise from defective
conversion of glucose into energy.
The plasma levels of FPG≥7.0mmol/L or PPG ≥11.1mmol/L
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Diabetes

Hyperglycemia result in widespread damage in
the body that can lead to hypertension, heart
disease, stroke, impaired circulation, nerve
dysfunction, pain, infection, or organ failure.

Clinical diabetes mellitus（糖尿病）occurs in two
forms, Type 1 and Type 2 , with different
causes and methods of therapy.
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Type 1 Diabetes (insulin-dependent)
Formerly known as insulin-dependent diabetes
mellitus (IDDM, 胰岛素依赖性糖尿病).
The β–cells of the pancreatic islets of
Langerhans (胰岛) are destroyed, probably by an
autoimmune process, such that insulin
production is grossly deficient（严重缺乏）.
There exists only a weak genetic link in the
etiology(病原学)of this form of diabetes.
Type 1 diabetes is invariably treated with insulin.
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Type 2 Diabetes (noninsulin-dependent)
Formerly known as noninsulin-dependent
diabetes mellitus (NIDDM).
Frequently associated with obesity(肥胖症)in its
mainly adult victims. Serum insulin levels are
normal or elevated, so in essence this is a
disease of insulin resistance.
There is a strong genetic link in the etiology（病
原学）of the condition, and insulin therapy is not
always required.
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Hypoglycemic Drugs
Treatments of Type 2 diabetes include：
(1) agents which increase the amount of
insulin secreted by the pancreas
(2) agents which increase the sensitivity of
target organs to insulin
(3) agents which decrease the rate at which
glucose is absorbed from the gastrointestinal
tract.
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Classification of Hypoglycemic Drug
 Sulfonylureas (磺酰脲类)
 Biguanides (双胍类)
α-Glucosidase inhibitors (α-葡萄糖苷酶抑制剂)
 Thiazolindiones (噻唑烷二酮类)
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Sulfonylureas(磺酰脲类)
 The hypoglycemic(降血糖)effect of salicylates(水杨酸
盐)has been known for 100 years. Clinical use of
salicylates was not feasible, since the very large doses
required produced intolerable side effects.
 The hypoglycemic effects of the thiadiazole
sulfonamide known as IPTD, used to treat typhoid (伤
寒症)fever in the 1940s. This drug produced many
deaths which were subsequently attributed to
prolonged drug-induced hypoglycemia.
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Sulfonylureas
 At same time these effects were noted, the synthesis
of sulfonylurea such as Carbutamide, so far active as
hypoglycemic agents, was reported.
 Since then, about 12, 000 sulfonylureas have been
tested, and about 10 are currently on the market.
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Sulfonylureas
1st generation
2nd generation
3rd generation
•
•
•
•
•
•
•
•
•
•
Tolbutamide
Chlorpropamide
Acetohexamide
Tolazamide
Gliclazide
Glibornuride
Glibenclamide
Glipizide
Gliquidone
Glimepiride
甲苯磺丁脲
氯磺丙脲
醋磺己脲
妥拉磺脲
格列齐特
格列波脲
格列本脲
格列吡嗪
格列喹酮
格列美脲
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First and second generation
sulfonylureas
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Tolbutamide (甲苯磺丁脲 )
O
O
O
S
N
H
N
H
1-Butyl-3-(p-tolylsulfonyl)urea
N-[(butylamino)carbonyl]-4-methylbenzenesulfonamide
White, crystalline powder, insoluble in water, soluble
in alcohol or aqueous alkali. It is stable in air.
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Acidic property
Tolbutamide shows acidic property，it can be
dissolved in base.
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odour
Unstable under acidic condition.
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Metabolism of Tolbutamide
 Tolbutamide is absorbed rapidly in responsive
diabetic patients. The blood sugar level reaches a
minimum after 5-8 h.
 It is oxidized rapidly in vivo to derivative with
hydroxyl group (I) or derivative with carboxyl group
(II), which are inactive.
O O
O
S
HO
N
H
N
H
I
O O
O
S
HO
O
N
H
N
H
II
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Synthesis of Tolbutamide
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Glibenclamide(格列本脲
)
1-[[p-[2-(5-chloro-o-anisamido)ethyl]-phenyl]sulfonyl]
-3-cyclohexylurea.
 Second-generation oral hypoglycemic agent.
 The drug has a half-life elimination of 10h, but its
hypoglycemic effect remains for up to 24h.
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Hydrolysis of Glibenclamide
O O O
S
N
N
H
H
O
Cl
N
H
O O O
+
S
N
N
H
H2
O
H+
Cl
N
H


+
O O
OH +
S
N C NH2
H
O-
O
Cl
N
H
H2 O

+
O O
OH2
S
N C
H
O
O
Cl
N
H
+

O O
S
NH2
O
Cl
N
H

H2N
+
CO2 + H+
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Glimepiride(格列美脲)
1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]
phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea.
 The third-generation oral hypoglycemic agent.
 Instead of the benzene ring found in Glibenclamide, Glimepiride
contains a pyrrolidine system.
 It is metabolized primarily through oxidation of the alkyl side chain
of the pyrrolidine, with a minor metabolic route involving
acetylation of the amine.
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Other Antidiabetic drugs:
Biguanide: (双胍)
 The most commonly used oral drug
for type 2 diabetes.
 Increasing insulin sensitivity.
 Decreasing the absorption of glucose
from the gastroinestinal tract.
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Discovery
 The guanidine derivatives（胍衍生物）Synthalin A
and B were introduced into therapy in the 1920s, but
chronic toxicity forced their abandonment in the
1930s.
 The widely used biguanides(双胍) Phenformin and
Metformin were prepared in the 1950s, and the latter
is still in widespread use.
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Metformin Hydrochloride（盐酸二甲双胍）
N，N-Dimethylimidodicarbonimidic diamide
hydrochloride
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Metformin
 Metformin was discovered in 1957，it was
not approved by the FDA until 1994 for the
treatment of type 2 diabetes.
 It is to lower blood glucose and to reduce
cardiovascular complications（并发症）.
 Over 6 million people were treated by it
annually.
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α-Glucosidase inhibitors
Miglitol (米格列醇)
O
OH
HO
HO
1-(2-Hydroxyethyl)-2(hydroxymethyl)piperidine3,4,5-triol
OH
OH
pyranose
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Miglitol
White to pale-yellow powder is soluble in water, and
exhibits a pKa 5.9.
 In chemical structure, this agent is very simliar to a
pyranose sugar (吡喃糖), with a nitrogen atom replacing the
oxygen isosterically.
α-Glucosidase takes it in as a substrate and is thereby
competitively inhibited.
 The end result is a delay in the absorption of complex
carbohydrates from the gastrointestinal tract.

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Thiazolindiones
Rosiglitazone Maleate (马来酸罗格列酮)
(噻唑烷二酮类)
O
H
COOH
H
COOH
NH
N
S
O
O

Chemical Name:
(5-[[4-[2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl]
-2,4-thiazolidinedione maleate
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Avandia 文迪雅
Function of Rosiglitazone Maleate
Rosiglitazone maleate is not chemically or
functionally related to the sulfonylureas, the
biguanides, or the alpha-glucosidase inhibitors.
It is an oral antidiabetic agent which acts
primarily by increasing insulin sensitivity.
It sales 3.6-3.8 billion USD in 2008.
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Side Effects
 It is reported in May 2007 that the use of rosiglitazone
was associated with a significantly increased risk of
heart attack, and an even higher risk of death from all
cardiovascular diseases.
 The FDA issued an alert on May 21, 2007.
 In 2009 the study found that there was no increase in
cardiovascular hospitalisation or death with rosiglitazone
compared to metformin plus sulfonylurea, but the rate of
heart failure causing admission to hospital or death was
significantly increased.
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Diuretics
(利尿剂)
Definition:
Diuretics are drugs that increase the rate
of urine formation.
More commonly known as “water pills”.
Some people use diuretics as a weight loss aid. This is not a
healthy way to lose weight. Abusing diuretics can lead to
dehydration and sometimes severe potassium deficiencies.
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Diuretics increase the rate of
urine formation by interfering
with the re-absorption of
sodium by the nephron (肾元).
There are four major
anatomical(解剖)sites along the
nephron that are responsible for
the bulk of Na+ re-absorption.
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Sodium Reabsorption Sites in the Nephron
65%
5%
Proximal Tubule
近端小管
Distal Tubule
远端小管
1
Collecting Tubule
集合小管
3
Glomerulus
肾小球
2
30%
Loop of Helen
细尿管袢
4
1-4%
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Four major anatomical(解剖学)sites
• Site 1: the convoluted and straight portions of
the proximal tubule(近端小管);
• Site 2: the thick ascending limb(升支)of Helen’s
loop;
• Site 3: the distal convoluted tubule(远曲小管);
• Site 4: the connecting tubule(集合小管) and the
cortical collecting tubule(皮质部集合小管).
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acetazolamide
acetazolamide
hydrochlorothiazide
Triamterene
3
1
2
furosemide
4
Spironolactone
fu
s
f
u
f
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Potency and efficacy of Diuretics
Diuretic efficacy has increased with the
corresponding changes in the site of action
of each of three classes of diuretics:
Weaker
Class 1, CA inhibitor:
Inhibit the reabsorption of Na+/HCO3-at site 1.
Class 2, Thiazide and thiazide-like diuretics:
Inhibit the reabsorption of Na+/Cl- at site 3.
Stronger
Class 3, High-ceiling diuretics:
Block Na+/Cl-/K+/Ca+/Mg2+ reabsorption at site 2.
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Class 1: Carbonic Anhydrase Inhibitors
Shortly after its introduction for the treatment of
bacterial infections, sulfanilamide was observed
to produce a mild diuresis characterized by
presence of urinary Na+ and a substantial
amount of HCO3-.
It induced this effect through inhibition of renal
carbonic anhydrase (碳酸酐酶，CA).
It was a relatively weak inhibitor of renal CA,
and the dose needed to exert adequate diuresis
was associated with severe adverse effects.
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CA inhibitor
 To improve on the CA-inhibitory property of
sulfanilamide, many sulfamoyl-containing
compounds (-SO2NH2) were synthesized.
 Two groups of CA inhibitors emerged:
simple heterocyclic sulfonamides and metadisulfamoylbenzene derivatives.
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Two groups of CA inhibitors
N N
H2NO2S
N N
NH C CH3
S
H2NO2S
S
O
CH3
N
C CH3
O
Methazolamide
Acetazolamide
Heterocyclic sulfonamide

H2NO2S
Sulfanilamide
meta-Disulfamoylbenzenes
Cl
Cl
H2NO2S
Cl
SO2NH2
Dichlorphenamide
H2NO2S
NH2
SO2NH2
Chloraminophenamide
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Common CA inhibitor
S
S
H2N
O
S
Cl
S
NH2
O
N
Chlorothiazide
NH
O
H2N
O
S
Cl
O
S O
NH2
N
Ethoxzolamide
O
S
O
S
NH2
Methazolamide
O
S
O
N N
O
Acetazolamide
O
S
N
N N
O
O
O
O
O
H
N
O
NH H2N
N
H
Hydrochlorothiazide
O
S
Cl
O
O
S
NH
N
H
Cl
Cl
Trichormethiazide
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Acetazolamide
H
N
O O
S
S
NH2
O
N N
 Name: （Diamox)
N-[5-(aminosulfony)-1,3,4-thiadiazol-2-yl]acetamide.
 White needle crystal, m.p. 258-259 ºC, soluble in
basic solution (NH3.H2O).
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Acetazolamide
 It was introduced in 1953 as the first orally
effective, non-mercurial diuretic available to the
physician.
 It has a relatively restricted use today because
of its limited efficacy and the refractoriness (失效)
that develops to its diuretic action within the first
week of continuous therapy.
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Mechanism of action
O
C
O
O
H
H
O
̼
Ëá
ôû
ø
S
N
O
H
H
̼
Ëá
ôû
ø
Similar structure
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Uses
 The major use of the CA inhibitors is in the treatment of
glaucoma (青光眼).
 CA is a functionally important enzyme in the eye, where
it plays a key role in the formation of aqueous humor (眼
球的水状体).
 As adjuvants(佐药)for the treatment of epilepsy(癫痫).
 Create an alkaline urine in an attempt to hasten the renal
excretion of certain noxious weak acids (uric acid).
 CA inhibitors have been used prophylactically(预防) to
counteract (抵抗) acute mountain sickness(急性高山病).
急性高山反应：由于在高海拔人呼吸急促，血液里氧气不足导致
了碳酸过多，碳酸过多引起轻微脑部水肿，结果是头疼和心。
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Class 2: Thiazide and Thiazide-like diuretics
O
O
O
O
H2NS
SNH2
Cl
NH2
Chloraminophenamide
Aldehydes
(or Ketones)
Acylating Agents
O
O
O
H2NS
O
O
O
H2NS
S
O
O
S
NH
NH
Cl
N
Thiazides
R
Cl
N
H
R
Hydrothiazides
(Hydrochlorothiazide)
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 Chloraminophenamide became a key intermediate in
the development of diuretics that lack the undesirable
properties of the CA inhibitors (???).
 When Chloraminophenamide was treated with acylating agents,
cyclization resulted in the formation of Thiazides. The use of
aldehydes or ketones in place of the acylating reagents yielded
the corresponding dihydro derivatives. The products of these
reactions became known as thiazides and hydrothiazides,
respectively.
 The thiazides were the first orally effective saluretic
agents（促尿食盐排泄药）whose diuretic activity was not
influenced by the patient’s acid-base status.
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Hydrochlorothiazide
 Name：6-Chloro-3,4-dihydro-2H-1,2,4benzothiadiazine-7-sulfonamide,1,1-dioxide
 It can be hydrolyzed in water.
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Synthesis of Hydrochlorothiazide
HOSO2Cl
Cl
NH2
O O
S
H2N
Cl
Cl
O O
S
Cl
O O
S
NH2
NH2
HCHO
HCl
O O
S
Cl
NH3.H2O
NH2
O O
S
H2N
Cl
O O
S
NH
N
H
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Class 3: High-ceiling or loop diuretics(髓袢利尿剂
Results from structure-activity relationship studies that
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led to the development of furosemide.
速尿
Furosemide
O O
H2N
O
S
Cl
OH
O
N
H
 Name:
5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl）
amino] benzoic acid
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Chemical property of Furosemide
 Acidic，pKa 3.9
Most effective,
Strongest diuretic!
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Metabolism
 The bioavailability of furosemide (orally) is about 60
to 69% in normal but only 43-46% in individuals
with end stage renal disease.
 A small percentage of furosemide is converted to the
corresponding glucuronide(葡萄糖醛酸苷), 88% of the
administered drug is excreted by kidneys and 1.9%
was metabolite as followed:
O
H2N
O
S
Cl
O
O
OH
NH
O
1.9%
H2N
O
S
Cl
O
OH
NH2
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Other: Potassium-sparing diuretics
A negative feature of all above-discussed
diuretics is that they increase the renal
excretion rate of K+ and thus can induce
hypokalemia(低钾血).
The K+-sparing diuretics including
Spironolactone and Triameterene.
Keep K+
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Spirolactones
Extremely mild diuretic
 Chemical name:
7-(Acetylthio)- 17  -hydroxy-3-oxopregn-4-ene-21carboxylic acid--lactone）
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Structure-Activity Relationships
 In the mid-1950s, it was observed that progesterone
(黄体酮) inhibited the anti-natriuretic (抗尿钠排泄) and
kaliuretic (尿钾排泄) effects of aldosterone (醛甾酮).
 An intensive effort was launched to develop steroidal
derivatives that possessed only the anti-mineral
ocorticoid (抗盐皮质激素) activity.
 Spironolactone was selected from a lot of derivatives
for further examination.
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Spironolactone and Canrenone competitively
inhibit the actions of aldosterone(醛甾酮)at site 4 and
are associated with a lower frequency of hormonal
side effects.
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