利尿药和降血糖药.ppt

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1、Medicinal chemistryChapter 10 Diuretics and Synthetic Hypoglycemic DrugsChapter 10 Diuretics and Synthetic Hypoglycemic DrugsSection 1 Hypoglycemic Drugs Section 2 Diuretics Section 1 Hypoglycemic DrugsThe The classic classic triad triad of of symptoms symptoms in in diabetes diabetes is is polyphag

2、iapolyphagia,polydypsiapolydypsia (thirst),(thirst),and and polyuriapolyuria (excess(excess urine).urine).All All three three result result directly directly from from excessive serum glucose levels.excessive serum glucose levels.Type Type 1 1 diabetes diabetes usually usually develops develops in i

3、n an an acute acute manner,manner,although although the the destructive destructive autoimmune autoimmune process may have been underway for some time.process may have been underway for some time.Type Type 2 2 diabetes diabetes has has a a more more insidious,insidious,often often asymptomatic asymp

4、tomatic onset onset and and its its presence presence is is usually usually detected by routine medical examinations.detected by routine medical examinations.Definitions Type I Diabetes.Insulin-dependent Insulin-dependent diabetes diabetes mellitus mellitus(IDDM),(IDDM),this this condition condition

5、 occurs occurs when when the the-cells cells of of the the pancreatic pancreatic islets islets of of LangerhansLangerhans are are destroyed,destroyed,probably probably by by an an autoimmune autoimmune process,process,such that insulin production is deficient.such that insulin production is deficien

6、t.Type 2 Diabetes.NoninsulinNoninsulin-dependent-dependent diabetes diabetes mellitus mellitus(NIDDM)(NIDDM)is is very very frequently frequently associated associated with with obesity obesity in in its its mainly mainly adult adult victims.victims.Serum Serum insulin insulin levels levels are are

7、normal normal or or elevated,elevated,so so in in essence this is a disease of insulin resistance.essence this is a disease of insulin resistance.Biochemistry and Pathogenesis of DiabetesClassifications First Generation First Generation SulfonylureasSulfonylureas:tolbutamidetolbutamide.Second Genera

8、tion Second Generation SulfonylureasSulfonylureas:glibenclamideglibenclamide.Third Third Generation Generation SulfonylureasSulfonylureas:glimepirideglimepiride,repagliniderepaglinide.BiguanidesBiguanides:metforminmetformin.-GlucosidaseGlucosidase Inhibitors:Inhibitors:AcarboseAcarbose,MiglitolMigli

9、tol.Mechanism of ActionSulfonylureas Sulfonylureas interact interact with with receptors receptors on on pancreatic pancreatic-cells-cells to to block block ATP-sensitive ATP-sensitive potassium channels.potassium channels.This This in in turn turn leads leads to to opening opening of of voltage-sen

10、sitive voltage-sensitive calcium calcium channels channels which which produces produces an an influx influx of of calcium;calcium;the the influx influx of of calcium calcium results results in in-cells-cells production of insulin.production of insulin.An An additional additional effect effect of of

11、 sulfonylureas sulfonylureas is is suppression of gluconeogenesis in the liver.suppression of gluconeogenesis in the liver.Physical-Chemical PropertiesSulfonylureas Sulfonylureas are are weak weak acids acids due due to to the the marked marked delocalization delocalization of of the the nitrogen ni

12、trogen lone lone electron electron pair pair by by the the sulfonyl sulfonyl group.group.Their Their pKas pKas cluster cluster around around 5.0 and they are strongly protein bound.5.0 and they are strongly protein bound.Structure-activity RelationshipsThere There must must be be reasonable reasonab

13、le bulk bulk on on the the urea urea nitrogen;nitrogen;methyl methyl and and ethyl ethyl compounds compounds are are not not active.active.Usually,Usually,there there is is only only one one(normally(normally substituent substituent para)on the sulfonyl aromatic ring.para)on the sulfonyl aromatic ri

14、ng.Many Many simple simple substituents substituents on on the the sulfonyl sulfonyl aromatic ring are active.aromatic ring are active.The The p-(p-(-arylcarboxamidoethyl)-arylcarboxamidoethyl)grouping grouping seen seen in in second second generation generation compounds compounds is is consistent

15、consistent with high potency.with high potency.It It is is thought thought that that the the spatial spatial relationship relationship between between the the amide amide nitrogen nitrogen of of the the substituent substituent and the sulfonamide nitrogen is important.and the sulfonamide nitrogen is

16、 important.TolbutamideN-(Butylamino)carbonyl-4-methylbenzene N-(Butylamino)carbonyl-4-methylbenzene sulfonamidesulfonamideButyl group on the urea nitrogen;Butyl group on the urea nitrogen;Para-methylbenzene on the sulfonyl group.Para-methylbenzene on the sulfonyl group.Properties Tolbutamide Tolbuta

17、mide have have sulfonylurea sulfonylurea structure structure with with weak weak acid,acid,and and this this property property may may be be used used for for assay.assay.Instability:Instability:Tolbutamide Tolbutamide is is hydrolyzed hydrolyzed to to para-para-toluene toluene sulfonamide sulfonami

18、de by by acids.acids.Heating Heating of of its its filtrate filtrate with with sodium sodium hydroxide hydroxide solution solution produces produces n-butylamine odour.n-butylamine odour.Metabolism Tolbutamide Tolbutamide is is metabolized metabolized in in the the liver liver to to p p-hydroxyl-hyd

19、roxyl tolbutamide,tolbutamide,retaining retaining about about 35%35%of of the the activity activity of of the parent compound.the parent compound.it it is is converted converted very very rapidly rapidly to to the the inactive inactive tolbutamide 4-carboxylic acid.tolbutamide 4-carboxylic acid.Glib

20、enclamide5-Chloro-N-2-4-(cyclohexylamino)carbonyl 5-Chloro-N-2-4-(cyclohexylamino)carbonyl aminosulfonylphenyl-2-methoxybenzamideaminosulfonylphenyl-2-methoxybenzamideIntroduction of cyclohexane on the urea nitrogen;Introduction of cyclohexane on the urea nitrogen;Introduction of side chain on the s

21、ulfonyl Introduction of side chain on the sulfonyl aromatic ring.aromatic ring.Properties It is not stable to moisture and is hydrolyzed to sulfamide derivate.MetabolismGlibenclamideGlibenclamide affords affords trans-4-hydroxy-glyburide trans-4-hydroxy-glyburide as the major product.as the major pr

22、oduct.The The 3-hydroxy 3-hydroxy metabolite metabolite retains retains about about 15%15%of of the activity of the parent compound.the activity of the parent compound.Therapeutic ApplicationIn In general,general,the the effects effects of of the the first-first-and and second-second-generation gene

23、ration sulfonylureas sulfonylureas are are similar.similar.All All produce produce reliable hypoglycemia in type 2 diabetics.reliable hypoglycemia in type 2 diabetics.These These agents agents work work best best in in patients patients whose whose type type 2 2 diabetes is relatively mild.diabetes

24、is relatively mild.Synthetic RouteThird-generation sulfonylureaGlimepiride Glimepiride is is a a sulfonylurea sulfonylurea with with a a quick quick onset onset of action and a long duration of action.of action and a long duration of action.It It may may bind bind to to a a different different prote

25、in protein in in the the putative putative sulfonylurea sulfonylurea receptor receptor than than earlier earlier drugs,drugs,and and may may exert exert its its hypoglycemic hypoglycemic effect effect with with less less secretion of insulin.secretion of insulin.Metformin hydrochloride N,N-Dimethyli

26、midodicarbonimidic diamide N,N-Dimethylimidodicarbonimidic diamide hydrochloridehydrochlorideMetformin,Metformin,Biguanides,Biguanides,has has been been in in use use throughout throughout the the world,world,with with the the exception exception of of the the U.S.,for decades.U.S.,for decades.Mecha

27、nism of ActionMetformin Metformin is is usually usually said said to to be be an an antihyperglycemic antihyperglycemic rather rather than than a a hypoglycemic hypoglycemic agent.agent.Overall,Overall,the the drug drug appears appears to to increase increase glucose utilization.glucose utilization.

28、Inhibition Inhibition of of gluconeogenesis gluconeogenesis appears appears to to be be an an important component of the drugs activity.important component of the drugs activity.Actions and UsesUnlike Unlike sulfonylureas,sulfonylureas,Metformin Metformin is is not not protein protein bound,bound,is

29、 is not not metabolized,metabolized,and and is is rapidly rapidly eliminated by the kidney.eliminated by the kidney.It It is is widely widely used used as as monotherapy monotherapy or or in in combination combination with with a a sulfonylurea sulfonylurea in in type type 2 2 diabetes,diabetes,part

30、icularly particularly when when the the patient patient is is obese obese and and insulin-insulin-resistant.resistant.-Glucosidase InhibitorsTo To be be absorbed absorbed from from the the gastrointestinal gastrointestinal tract tract into into the the bloodstream,bloodstream,the the complex complex

31、 carbohydrates carbohydrates we we ingest ingest as as part part of of our our diet diet must must first first be be hydrolyzed hydrolyzed to to monosaccharides.monosaccharides.The The rationale rationale for for thethe-glucosidase-glucosidase inhibitor inhibitor is is that that by by preventing pre

32、venting the the hydrolysis hydrolysis of of carbohydrates carbohydrates their their absorption could be reduced.absorption could be reduced.Metabolism of complex carbohydrades Section 2 DiureticsDiuretics Diuretics are are chemicals chemicals that that increase increase the the rate rate of of urine

33、 formation.urine formation.Diuretic Diuretic usage usage leads leads to to the the increased increased excretion excretion of of electrolytes electrolytes(especially(especially sodium sodium and and chloride chloride ions)ions)and and water water from from the the body body without without affecting

34、 affecting protein,protein,vitamin,vitamin,glucose glucose or or amino amino acid acid reabsorption.reabsorption.Structure ClassificationThe The diuretics diuretics currently currently in in use use today today are are classified classified as follows:as follows:Thiazides(by their chemical classes);

35、Thiazides(by their chemical classes);Carbonic Carbonic anhydrase anhydrase inhibitors,inhibitors,osmotics osmotics(by(by mechanism of action);mechanism of action);Loop diuretics(by site of action);Loop diuretics(by site of action);Potassium-sparing Potassium-sparing diuretics diuretics(by(by effects

36、 effects on on urine urine contents).contents).Furosemide5-(Aminosulfonyl)-4-chloro-2-(2-furanylmethyl)5-(Aminosulfonyl)-4-chloro-2-(2-furanylmethyl)amino benzoic acid amino benzoic acidFurosemide is an example of a high-ceiling Furosemide is an example of a high-ceiling diuretic and may be regarded

37、 as a derivative of diuretic and may be regarded as a derivative of anthranilic acids.anthranilic acids.Structure-activity RelationshipsThe The chlorine chlorine and and sulfonamide sulfonamide substitutions substitutions are are features of this class drugs.features of this class drugs.Furosemide F

38、urosemide is is a a stronger stronger acid acid than than the the thiazide thiazide diuretics(pKa 3.9).diuretics(pKa 3.9).This This drug drug is is excreted excreted primarily primarily unchanged.unchanged.A A small small amount amount of of metabolism,metabolism,however,however,can can take take pl

39、ace on the furan ring.place on the furan ring.Therapeutic ApplicationsFurosemide Furosemide has has a a saluretic saluretic effect effect 8-10 8-10 times times that that of of the the thiazide thiazide diuretics,diuretics,however,however,it it has has a a shorter shorter duration of action,about 6-8

40、 hours.duration of action,about 6-8 hours.It It is is effective effective for for the the treatment treatment of of edemas edemas connected with cardiac,hepatic,and renal sites.connected with cardiac,hepatic,and renal sites.Clinical Clinical toxicity toxicity of of furosemide furosemide involves inv

41、olves abnormalities of fluid and electrolyte balance.abnormalities of fluid and electrolyte balance.Hydrochlorothiazide6-Chloro-3,4-dihydro-26-Chloro-3,4-dihydro-2H H-1,2,4-benzothiadiazine-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide7-sulfonamide 1,1-dioxideThe The thiazide thiazide diuretics d

42、iuretics are are weakly weakly acidic acidic with with a a benzothiadiaze 1,1-dioxide nucleus.benzothiadiaze 1,1-dioxide nucleus.Mechanism of ActionThe The major major site site of of action action of of these these compounds compounds is is in in the the distal distal tubule,tubule,where where thes

43、e these drugs drugs compete compete for for the the chloride chloride binding binding site site of of the the NaNa+-C1-C1-symporter symporter and and inhibit inhibit the the reabsorption reabsorption of of sodium sodium and and chloride ions.chloride ions.They They also also inhibit inhibit the the

44、reabsorption reabsorption of of potassium potassium and bicarbonate ions but to a lesser degree.and bicarbonate ions but to a lesser degree.Structure-activity RelationshipThe The hydrogen hydrogen atom atom at at the the 2-N 2-N is is the the most most acidic.acidic.These These acidic acidic protons

45、 protons make make possible possible the the formation formation of a water-soluble sodium salt.of a water-soluble sodium salt.An An electron-withdrawing electron-withdrawing group group is is necessary necessary at at position 6 for diuretic activity.position 6 for diuretic activity.Replacement Rep

46、lacement or or removal removal of of the the sulfonamide sulfonamide at at position position 7 7 yields yields compounds compounds with with little little or or no no diuretic activity.diuretic activity.Saturation Saturation of of the the double double bond bond to to give give a a 3,3,4 4 dihydro d

47、ihydro derivative derivative produces produces a a diuretic diuretic that that is is 10 10 times more than the unsaturated derivative.times more than the unsaturated derivative.Substitution Substitution lipophilic lipophilic group group at at position position 3 3 gives gives a a marked marked in in

48、 the the diuretic diuretic potency potency with with a a longer longer duration of action.duration of action.Alkyl Alkyl substitution substitution on on the the 2-N 2-N position position also also decreases decreases the the polarity polarity and and increases increases the the duration duration of

49、diuretic action.of diuretic action.Therapeutic ApplicationsHydrochlorothiazideHydrochlorothiazide is is indicated indicated in in the the management management of of hypertension hypertension either either as as the the sole sole therapeutic therapeutic agent,agent,or or in in combination combinatio

50、n with with other antihypertensives.other antihypertensives.AcetazolamideN-5-(Aminosulfonyl)1,3,4-thiadiazol-2-ylN-5-(Aminosulfonyl)1,3,4-thiadiazol-2-yl acetamide acetamideAcetazolamide Acetazolamide was was the the first first of of the the carbonic carbonic anhydrase anhydrase inhibitors inhibito