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Chapter 10 Chapter 10 Diuretics and Synthetic Diuretics and Synthetic Hypoglycemic DrugsHypoglycemic Drugs

Pei YuPei Yu College of pharmacyCollege of pharmacy Jinan UniversityJinan University

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Synthetic Hypoglycemic AgentsSynthetic 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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DiabetesDiabetesHyperglycemia 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 (Type 1 Diabetes (insulin-dependentinsulin-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 (Type 2 Diabetes (noninsulin-dependentnoninsulin-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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88

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Hypoglycemic DrugsHypoglycemic Drugs

Treatments of Type 2 diabetes include ： (1) agents which increase the amount of insuli

n 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 DrugClassification 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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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-ind

uced hypoglycemia.

SulfonylureasSulfonylureas(( 磺酰脲类 )

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SulfonylureasSulfonylureas

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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SulfonylureasSulfonylureas• Tolbutamide 甲苯磺丁脲• Chlorpropamide 氯磺丙脲• Acetohexamide 醋磺己脲• Tolazamide 妥拉磺脲• Gliclazide 格列齐特• Glibornuride 格列波脲• Glibenclamide 格列本脲• Glipizide 格列吡嗪• Gliquidone 格列喹酮• Glimepiride 格列美脲

1st generation

2nd generation

3rd generation

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First and second generation sulfonylurFirst and second generation sulfonylureaseas

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Tolbutamide Tolbutamide (( 甲苯磺丁脲 甲苯磺丁脲 ))

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.

S

NH

NH

O O O

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Acidic propertyAcidic property Tolbutamide shows acidic property ， it can b

e dissolved in base.

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Unstable under acidic condition.Unstable under acidic condition.

odour

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Metabolism of Metabolism of TolbutamideTolbutamideTolbutamide is absorbed rapidly in responsive diabeti

c 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.

SNH

NH

O O O

HO

SNH

NH

O O O

HO

OI II

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Synthesis of Synthesis of TolbutamideTolbutamide

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GlibenclamideGlibenclamide(( 格列本脲 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 hypogly

cemic effect remains for up to 24h.

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Hydrolysis of GlibenclamideHydrolysis of Glibenclamide

NH

SNH

NH

Cl

O

O O O

NH

SNH

NH2Cl

O

O O O+

NH

SNH

Cl

O

O O

C NH2

OH

O-

+

+

NH

SNH

Cl

O

O O

C

OH2

O

+

H2N

NH

SNH2

Cl

O

O O

CO2 H+

H+

H2O

+

+ +

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GlimepirideGlimepiride(( 格列美脲格列美脲 ))

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 con

tains 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:Other Antidiabetic drugs:

Biguanide: (( 双胍双胍 ))

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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DiscoveryDiscoveryThe 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 HydrochlorideMetformin Hydrochloride （盐酸二甲双胍）（盐酸二甲双胍）

N ， N-Dimethylimidodicarbonimidic diamide

hydrochloride

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MetforminMetformin

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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αα-Glucosidase inhibitors-Glucosidase inhibitorsMiglitol Miglitol (( 米格列醇 )

1-(2-Hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

O

HO

HO

OH

OH

OH

pyranose

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MiglitolMiglitol 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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ThiazolindionesThiazolindiones (( 噻唑烷二酮类噻唑烷二酮类 ))

Rosiglitazone Maleate Rosiglitazone Maleate (( 马来酸罗格列酮 )

N

O

S

NH

O

O

COOH

COOH

H

H

Chemical Name:(5-[[4-[2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl] -2,4-thiazolidinedione maleate

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Function of Rosiglitazone MaleateFunction 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.

Avandia 文迪雅

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Side EffectsSide EffectsIt 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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DiureticsDiuretics(( 利尿剂 )

Definition: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 anatomic

al( 解剖 )sites along the nephron t

hat are responsible for the bulk

of Na+ re-absorption.

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Sodium Reabsorption Sites in the Nephron

Proximal Tubule近端小管 Distal Tubule

远端小管

30%

5%

1-4%Loop of Helen细尿管袢

Collecting T

ubule集

合小

管

Glomerulus肾小球

1

42

3

65%

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Four major anatomicalFour major anatomical(( 解剖学 )sitessites• 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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acetazolamideacetazolamide hydrochlorothiazide Triamterene

Spironolactonesfuf

fu

furosemide

1

2

3

4

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Potency and efficacy of DiureticsPotency and efficacy of Diuretics

Class 1, CA inhibitor:Inhibit the reabsorption of Na+/HCO3

-at site 1.

Diuretic efficacy has increased with the corresponding changes in the site of action of each of three classes of diuretics:

Class 2, Thiazide and thiazide-like diuretics: Inhibit the reabsorption of Na+/Cl- at site 3.

Class 3, High-ceiling diuretics:Block Na+/Cl-/K+/Ca+/Mg2+ reabsorption at site 2.

Stronger

Weaker

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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.

Class 1:Class 1: Carbonic Anhydrase Inhibitors Carbonic Anhydrase Inhibitors

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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 meta-

disulfamoylbenzene derivatives.

CA inhibitor

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Two groups of CA inhibitors

H2NO2S

Sulfanilamide

NN

SH2NO2S NH C

O

CH3

NN

SH2NO2S N C

O

CH3

CH3

Acetazolamide Methazolamide

Heterocyclic sulfonamide

meta-DisulfamoylbenzenesCl

Cl

SO2NH2H2NO2S

Cl

SO2NH2H2NO2S

NH2

Dichlorphenamide Chloraminophenamide

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Common CA inhibitorCommon CA inhibitor

N N

S SNH2

HN

O

O O

Acetazolamide

N N

S SNH2

N

O

O O

Methazolamide

N

SO

S

NH2

OO

Ethoxzolamide

N

NHSS

H2N

Cl

OO O O

Chlorothiazide

NH

NHSS

H2N

Cl

OO O O

Cl

Cl

Trichormethiazide

NH

NHSS

H2N

Cl

OO O O

Hydrochlorothiazide

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AcetazolamideAcetazolamide

Name: （ Diamox) N-[5-(aminosulfony)-1,3,4-thiadiazol-2-yl]acetamide.White needle crystal, m.p. 258-259 ºC, soluble in basi

c solution (NH3.H2O).

N

S

N

HN S

O O

NH2

O

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AcetazolamideAcetazolamide 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 actionMechanism of action

̼Ëáôûø

CO O H

O H ̼Ëáôûø

H

SO N H

O

Similar structure

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UsesUsesThe 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:Class 2: Thiazide and Thiazide-like diuretics Thiazide and Thiazide-like diuretics

SNH2H2NS

NH2Cl

OOOO

Acylating AgentsAldehydes(or Ketones)

SH2NS

NCl

OOOO

NH

R

SH2NS

NH

Cl

OOOO

NH

R

Chloraminophenamide

Thiazides 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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HydrochlorothiazideHydrochlorothiazide

Name ： 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide,1,1-dioxide

It can be hydrolyzed in water.

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Synthesis of HydrochlorothiazideSynthesis of Hydrochlorothiazide

NH2 NH2

SSClCl

OOOO

Cl Cl

NH2

SSNH2H2N

OOOO

Cl

SSNHH2N

OOOO

Cl NH

HOSO2Cl NH3.H2O

HCHO

HCl

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Class 3:Class 3: High-ceiling or loop diuretics High-ceiling or loop diuretics(( 髓袢利尿剂 )

Results from structure-activity relationship studies that led to the development of furosemide.

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FurosemideFurosemide

Name:

5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl ） amino] benzoic acid

S

OO

H2N

Cl

O

OH

NH

O

速尿

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Chemical property of FurosemideFurosemide

Acidic ， pKa 3.9

Most effective,Strongest diuretic!

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MetabolismMetabolismThe 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:

Cl

OHSH2N

OO

NHCl

OHSH2N

OO

NH2

O

OO

1.9%

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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.

Other:Other: Potassium-sparing diuretics Potassium-sparing diuretics

Keep K+

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SpirolactonesSpirolactones

Chemical name:

7-(Acetylthio)- 17 -hydroxy-3-oxopregn-4-ene-21-carboxylic acid--lactone ）

Extremely mild diuretic

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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.

Structure-Activity RelationshipsStructure-Activity Relationships

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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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