Medicinal Chemistry

1. Medicinal Chemistry Dr. Jehad Harbali IUST College of Pharmacy

2. DIURETICS

3. DIURETICS A diuretic is defined as: achemical that increases the rate of urine formation. ►The primary action of most diuretics is the direct inhibition of Na+ transport at one or more of the four major anatomical sites along the nephron where Na+ reabsorption takes place: 1- Proximal convoluted tubule 2- Thick ascending Limb 3- Distal convoluted tubule 4- Cortical collecting tubule. Convoluted: ملفوف، ملتف، معقد Thick ≠ Thin : ثخين، سميك

4. Anatomy and Physiology of the Nephron The functional unit of the kidney is thenephron with its accompanying glomerulus. There are approximately A million nephrons in Each kidney. The structure of a Kidney nephron

5. Anatomy and Physiology of the Nephron The blood (or more appropriately, the plasma), from which all urine is formed, is brought to each nephron within the glomerular capillarynetwork.

6. Anatomy and Physiology of the Nephron ■Many plasma components are filtered into Bowman’sspace. ■ During the process of urine formation, the resulting glomerular filtrate flows through the convoluted and straight portions of the proximal tubule, descending limb of Henle’s loop, thin and thick portions of the ascending limb of henle’s loop, area of the macula densa cells, distal convoluted tubule (known also as early distal tubule), connecting tubule (also referred to as the late distal tubule), and the cortical and medullary collecting tubules.

7. Urine Formation ■As blood is delivered to each glomerulus, many (but not all) of its components are filtered into Bowman’s space through the “pores” in the glomerular capillary loops. ■ Urine is formed by three mechanisms: 1- glomerular filtration, 2- Tubular reabsorption, 3- Tubular secretion. ■ glomerular filtration: Each minute only 1 mL of urine is formed from the 125 mL of glomerular filtrate. Thus, approximately 99 % of the glomerular filtrate is normally reabsorbed.

8. Urine Formation ■There are four major anatomical sites along the nephron that are responsible for the bulk of Na+ reabsorption: 1- site (1), the convoluted and straight portions of the proximal tubule; 2- site (2), the thick ascending limb of Henle’s loop; 3- site (3), the distal convoluted tubule; 4- site (4), the connecting tubule and the cortical collecting tubule. ■ The class of diuretics that inhibit the reabsorption ofNa+ at sites 1, 2, or 3 ultimately increase, to varying degrees, the luminal fluid flow rate and the percentage of the filtered load of Na+ delivered to site 4. ■ Thus, many diuretics acutely enhance the urinary loss of K+and many be associated with the induction of hypokalemia.

9. Introduction to the Diuretics: ■ The potency of a diuretic is related to the absolute amount of drug (e.g. milligrams or milligram per kilogram) required to produce an effect. ■ The potency of a diuretic is influenced by its absorption, distribution, biotransformation, excretion, and inherent ability to combine with its receptor (its intrinsic activity). ■ Efficacy relates to the maximal diuretic effect attainable (usually measured in terms of urine volume per unit of time, or urinary loss of Na+or NaCl per unit of time). Numerous factors contribute to the efficacy of a diuretic.

10. Introduction to the Diuretics: ■ First, the anatomical site of action and the capacity of theNa+reabsorbing sites downstream play major roles in determining the overall efficacy. ■ That is, a diuretic’s efficacy is determined in part by whether it acts at site 1, 2, 3 or 4. ■ Diuretics that inhibit the reabsorption of Na+ at the same anatomical site are usually equiefficacious ( so, evoke similar maximal responses) but may vary in potency (the amount of diuretic necessary to produce similar effects). ■ The efficacy of a diuretic depends on its concentration at the site where it inhibitsNa+transport.

11. Mechanism of action of Carbonic Anhydrase ■ Carbonic Anhydrase catalyses, in the tubular cell, the following reaction: CO2 + H2OH2CO3HCO3-+ H+ Then, the bicarbonate molecule reabsorbed in the blood, and the H+ion pass to the luminal fluid causing acidification of the urinary filtrate.

12. Sites of action of Diuretics Distal tubule Proximal tubule Glomerulus Collecting tubule Henle’s loop

13. Site 1 Diuretics : Carbonic Anhydrase Inhibitors ■ CA inhibitors are used infrequently as diuretics, they play an important role in the development of other major classes of diuretics that are curently in widespread use. ■ Shortly after its introduction for the treatment of bacterial infections, sulfanilamide was observed to produce a mild diuresis characterized by the presence of urinaryNa+and a substantial amount ofHCO3- . ■ It was subsequently shown that it induced this effect through inhibition of renal CA, but it was a relatively weakinhibitor of renal CA.

14. Site 1 Diuretics : Carbonic Anhydrase Inhibitors ■To improve on the CA-inhibitory property of sulfanilaminde, many sulfamoyl-containing compounds (-SO2-NH2) were synthesized and screened for their diuretic activity in vivo and their ability to inhibit CA in vitro. ■Two groups of CA inhibitors emerged: = Simple heterocyclic sulfonamides, = meta- disulfamoylbenzene derivatives. ■ SAR studies involving the simple heterocyclic sulfonamides yielded the prototypic CA inhibitor, Acetazolamide.

15. Site 1 Diuretics : Carbonic Anhydrase Inhibitors ■ The sulfamoyl group is essential for in vitro CA-inhibitory activity and for diuresis production in vivo. ■ The sulfamoyl nitrogen atom must remain unsubstituted to retain both in vivo and in vitro activity. This feature explains why all antibacterial sulfonamides exceptSulfanilamideare incapable of inhibiting CA or exerting diuresis. ■ In contrast, substitution of a methyl group on one of Acetazolamide’s ring nitrogens yields Methazolamide, a product that retains CA-inhibitory activity. ■ The moiety to which the sulfamoyl group is attached must possess aromatic character.

16. Site 1 Diuretics : Carbonic Anhydrase Inhibitors ■ Within a given series of heterocyclic sulfonamides, the derivatives with the highest lipid/water partition coefficients and the lowest PKa values, have the greatest CA-inhibitory and diuretic activities. ■ The clinically available CA inhibitors are absorbed well from the GI tract, are distributed to the sites of major importance for CA inhibition, undergo little, if any biotransformation, and are excreted primarily by the kidneys.

17. Site 1 Diuretics : Carbonic Anhydrase Inhibitors

18. Site 1 Diuretics : Carbonic Anhydrase Inhibitors

19. Site 1 Diuretics : Carbonic Anhydrase Inhibitors ►Substitution with an amino (-NH2) group increases saluretic activity, but decreases carbonic Anhydrase inhibitory activity. ►Maximal diuretic activity is observed when this position is substituted with:Cl- , Br- , CF3- , or NO2-

20. Site 1 Diuretics : Carbonic Anhydrase Inhibitors ► H2N-O2S— :An unsubstituted sulfamoyl moiety is of paramount importance. ► The sulfamoyl moiety can be replaced with a similarly electrophilic group (e.g., carboxyl, carbamoyl) that may increase diuretic potency while decreasing carbonic anhydrase inhibitory activity.

21. Site 1 Diuretics : Carbonic Anhydrase Inhibitors ■ CA is located both intracellularly (type II CA) and in the luminal brush border membrane (type IV CA) of proximal convoluted tubule cells. Both of these site 1 locations are major targets of the CA inhibitors. ■ Four highly predictable adverse effects are associated with the CA inhibitors: 1- Development of metabolic acidosis due to the renal loss of HCO3- 2- Hypokalemia due to the renal loss of K+, 3- Up to a 20% reduction in the GFR, 4- Typical sulfonamide-associated hypersensitivity reactions, such as urticaria, drug fever, blood dyscrasias, and interstitial nephritis. urticaria: شرى blood dyscrasia : خلل في مكونات الدم interstitial nephritis: التهاب النيفرونات الخلالي

22. Site 1 Diuretics : Uses ■ The major use of the CA inhibitors is in the treatment of glaucoma. CA is a functionally important enzyme in the eye, where it plays a key role in the formation of aqueous humor. ■ Inhibition of this ocular enzyme reduces the rate of formation of the aqueous humor, thereby reducing the intraocular pressure associated with glaucoma. ■ CA inhibitors have been used prophylactically to counteract acute mountain sickness, to act as adjuvants for the treatment of epilepsy, and to create an alkaline urine in an attempt to hasten the renal excretion of certain noxious weak acids or to maintain the urinary solubility of certain poorly water soluble, endogenous weak acids (e.g. Uric Acid). Hasten: to make sth. Happen more quickly

23. Site 1 Diuretics : products ■ Acetazolamide (DIAMOXR):It was introduced in 1953 as the 1st orally effective diuretic.It has relatively restricted use today because of its limited efficacy, but it serves as the prototypic agent in its class. It is well absorbed from the GI tract, extensively bound to plasma proteins, and is not biotransformed. Peak plasma levels are attained within 2 to 4 hours. Its onset of action is about 1 h, and its duration of action ranges from 6 to 12 h.It is removed totally from the plasma by the kidney within 24 hours.

24. Site 1 Diuretics : products ■ Methazolamide (NEPTAZANER): a more potent CA inhibitor than Acetazolamide. It is seldom used as a diuretic, but displays improved penetration into eye. So it is used for the treatment of glaucoma. ■ Dichlorphenamide (DARANIDER): It is seldom used as a diuretic. It reduces intraocular pressure and may be useful in the treatment of glaucoma. Seldom: not often. Glaucoma: زرق

25. Methazolamide • Methazolamide [ N-(4-methyl-2-sulfamoyl-1,3,4-thiadiazol-5-yliden) acetamide] • It is made by an intermediate product of acetazolamide. • Action of this drug is similar to that of acetazolamide, and it is used for lowering intraocular pressure in treating wide-angle and secondary glaucoma, and before surgical intervention for severe wide-angle glaucoma. Synonyms of this drug are Naptazane and others.

26. Methazolamide • MethazolamideSynthesis: 2-acetylamino-5-mercapto-1,3,4-thiadiazol is benzylated with benzylchloride at the mercapto group, forming 2-acetylamino-5-benzylthio-1,3,3-thiadiazole. Further methylation of the product with methyl iodide leads to the formation of N-(4-methyl-2-benzylthio-1,3,4-thiadiazol-5-yliden) acetamide. • Oxidation and simultaneous chlorination of the resulting product with chlorine in an aqueous solution of acetic acid, and reacting the resulting chlorosulfonic derivative with ammonia gives Methazolamide

27. Site 3 Diuretics : Thiazide and Thiazide-like Diuretics ■ Chloraminophenamide becomea logical key intermediate in the development of diuretics that lacked the undesirable properties of the CA inhibitors. ■ The use of aldehydes or ketones in place of the acylating reagents yielded the corresponding dihydro derivatives. The products of these reactions become known as Thiazides and Hydrothiazides. ■ The Thiazideswere the 1st orally effective saluretic agents whose diuretic activity was not influenced by the patient’s acid- base status.

28. Site 3 Diuretics : SAR ■ The 2 position can tolerate the presence of relatively small alkyl groups, such as -CH3. ■ Sustituents in the 3 position play a dominant role in determining the potency and duration of action of the Thiazide diuretics.

29. Site 3 Diuretics : SAR ■ Loss of carbon–carbon double bond between the 3- 4 positions of the benzothiadiazine-1,1-dioxide nucleus, increases the potency of this class of diuretics approximately 3-10 fold. ■ Direct substitution of the 4, 5 or 8 position with an alkyl group usually diminishes diuretic activity. ■ Substitution at the 6 position with an “activating” group is essential for diuretic activity. The best Substituents include Cl-, Br-, CF3-, and NO2- groups. ■ The sulfamoyl group in the 7 position is a prerequisite for diuretic activity. Prerequisite: متطلب أساسي

30. Chlorothiazide • The diuretic action of chlorothiazide, like other drugs of this series, is caused by reduced absorption of sodium and chloride ions by the kidneys during their simultaneous, intense excretion from the organism. • This drug exhibits strong diuretic action during both acidosis and alkalosis. It is used for arterial hypertension, in edematous syndromes of various genesis effects in cardiovascular insufficiency, nephrosis and nephritis, and toxicosis. • It is especially recommended or hypertonic illnesses. It lowers intraocular pressure in a number of cases. Synonyms of this drug are DIUPRESR, DIURILR, and others.

31. Chlorothiazide • Chlorothiazide (1,1-dioxide 6-chloro-2H-1,2,4-benzothiadiazin-7-sulfonamide • It is synthesized in the exact same manner, is all thiazide diuretics. 3-chloroaniline (or trifluoromethylaniline) undergoes sulfoylchlorination by chlorosulfonic acid, forming 4,6-sulfonochloride-3-chloroaniline, the reaction of which with ammonia gives 4,6-sulfonylamido-3-chloroaniline. • Heating this with formamide leads to formation of chlorothiazide.

32. HydroChlorothiazide • Hydrochlorothiazide(1,1-dioxide 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-sulfonamide). • It is synthesized either by cyclization of 4,6-sulfonamide-3-chloroaniline using paraformaldehyde, during which simultaneous reduction of the double bond occurs at position C3-C4, or by reduction of the same double bond in chlorothiazide by formaldehyde. • This small change in structure increases activity of the drug in comparison with chlorothiazide, and increases its absorbability when used orally.

33. Site 3 Diuretics : SAR Thiazide Diuretics

34. Hydrothiazide Diuretics Site 3 Diuretics : SAR

35. Site 3 Diuretics : Pharmacokinetics ■ They are absorbed well after oral administration, except Chlorothiazide (only about 10% of which is absorbed). ■ Their onset of action usually occurs within 1 to 2 hours, and their peak diuretic effect is expressed within 3 to 6 hours. ■ The diuretics in this class differ primarily in potency and duration of action. Many of the diuretics in this class have long half-lives. ■ All of these diuretics block the reabsorption ofNa+(and thereby, the reabsorption ofCl-) in the distal convoluted tubules by inhibiting the luminal membrane- boundNa+/Cl- co-transport system.

36. Site 3 Diuretics : Adverse Effects ■ Four of the adverse effects associated with the Thiazide and Thiazide-like diuretics are highly predictable:1- All of these diuretics possess a sulphamoyl moiety, which has been associatedwith hypersensitivity reactions such as Urticaria, drug fever, blood dyscrasias, and interstitial nephritis. 2-Hypokalemia is a product of the diuretic-induced increase in the renal excretion ofK+ 3- They produce a slight reduction in the cardiac output, slight reductions in plasma volume and blood pressure occur with continued use. 4-Hpercalcemia or hyperuricemia after long-term use. blood dyscrasia: خلل في مكونات الدم interstitial nephritis: التهاب النيفرونات الخلالي

37. Site 2 Diuretics : High-Ceiling or Loop Diuretics ■ The diuretics in this class have extremely diverse chemical structures. Brief mention is made of the Organomercurial diuretics, and primary attention is focused on the agents with clinical utility: for example, Furosemide, Bumetanide, Torsemide, and Ethacrynic acid. a)Organomercurials, b) 5- Sulfamoyl-2-aminobenzoic Acid, and 5- Sulfamoyl-3-aminobenzoic Acid Derivatives, c) 4-amino-3-pyridinesulfonylureas, d) Phenoxyacetic Acids, Ceiling: a top limit or part of the convoluted tubule الحد الأعلى من اللفيف :.

38. Site 2 Diuretics : High-Ceiling or Loop Diuretics a)Organomercurials: they elicit diuresis by inhibiting Na+reabsorption at site 2, and they are natriuretic and chloruretic and minimal kaliuretic. All of these agents are orally effective, equally effective in both acidotic and alkalotic conditions, capable of inducing relatively rapid diuresis when given parenterally, and relatively nontoxic. b) 5- Sulfamoyl-2-aminobenzoic Acid, and 5- Sulfamoyl-3-aminobenzoic Acid Derivatives: 1- Bumetanide (BUMEXR): 2- Furosemide (LASIXR): Bumetanide Furosemide

39. Site 2 Diuretics : High-Ceiling or Loop Diuretics ■ Furosemide and Bumetanide differ pharmacologically primarily in their potencies and bioavailabilities. Bumetanide is more potent than Furosemide. ■ After parenteral administration, both have an extremely rapid onset of action (3 to 5 min.). Duration of action following parenteral therapy is 2 hours for Furosemide and 3.5 to 4 hours for Bumetanide.

40. Site 2 Diuretics : High-Ceiling or Loop Diuretics 5- Sulfamoyl -2 aminobenzoic Acids

41. Site 2 Diuretics : High-Ceiling or Loop Diuretics 5- Sulfamoyl - 3 aminobenzoic Acids

42. Furosemide • Furosemide is a highly effective and quick-acting diuretic whose action, like all of the examined loop diuretics, is associated with blocking reabsorption of ions in the ascending bend of Henle’s loop. • It is used for edema syndrome of various origins, edema of the lungs and brain, chronic renal insufficiency, some forms of hypertonic crises, and poisoning by barbiturates and other compounds excreted mainly with urine. • In a number of cases, furosemide has proven more effective than other diuretics. Besides a diuretic effect, it also dilates peripheral vessels. It is frequently used in combination with other antihypertensive drugs. • Synonyms of this drug are LAZIX, LAZIZIX, FRANIL, UROSEMIDE, and many others.

43. Furosemide • Furosemide(4-chloro-N-furfuryl-5-sulfamoylanthranylic acid). • It is synthesized in a relatively simple manner from 2,4-dichlorobenzoic acid, which is converted into 5-aminosulfonyl-4,6-dichlorobenzoic acid during subsequent reaction with chlorosulfonic acid and ammonia. Reacting this with furfurylamine gives Furosemide.

44. Site 2 Diuretics : High-Ceiling or Loop Diuretics ■ Both diuretics have an onset of action of approximately 30-60 min. after oral therapy, but F. has a slightly longer duration of action than B. (6 to 8 hours versus 4 to 6 hours). ■ Side effects: Hypokalemic alkalosis, reduced plasma volume in long-term treatment, symptoms of gout, and hypersensitivity reactions (urticaria, drug fever, blood dyscrasias, interstitial nephritis). • Gout: داء النقرس • blood dyscrasia: خلل في مكونات الدم • interstitial nephritis: التهاب النيفرونات الخلالي

45. c)4-amino-3-pyridinesulfonylureas: = Torsemide (DEMADEXR): a closely related structurally to Triflocin, a loop diuretic that was studied extensively in the late 1960’s, but abandoned because it produced transitional cell carcinoma in the urinary bladders of over 50% of the rats that had received high doses over an 18-22 month period. Torsemideis useful in the treatment Of mild-to-moderate hypertension In doses of 2.5-5 mg/once daily. 10-20 mg are used to treat edema Associated with congestive heart Failure and cirrhosis of the liver. Site 2 Diuretics : High-Ceiling or Loop Diuretics

46. Site 2 Diuretics : High-Ceiling or Loop Diuretics d)Phenoxyacetic Acids: they was developed and introduced into clinicaluse about the same time as Furosemide.= Ethacrynic Acid (EDECRINR): Certain organomercurialscan elicit a diuretic response, but because of their heavy metal content, they are too toxic for widespread use. After oral administration, onset of action is about 30 min. and duration of action is 6 to 8 hours. After parenteral administration, onset of action and duration of action are 3 - 5 min. and 2 - 3 hours. It is highly bound to plasma proteins (>95%), and excreted by the kidneys. It has the same indications of Furosemide and Bumetanide.

47. Site 2 Diuretics : High- Ceiling or Loop Diuretics

48. Miscellaneous Site 2 Diuretics: ■ Three nondiuretic agents are biotransformed to high-ceiling diuretics in vivo by sulfation of their –OH moieties. ■ The sulfated metabolites exert a diuresis by inhibition of the 1Na+ / 1K+ / 2Cl- co-transport system on the luminal membrane of thick ascending limb cells. ■ These agents include: CRE 10904:2-(p-fluorophenoxy), 1-(O-hydroxyphenyl) ethane, MK-447 :2-(aminomethyl)-4-(1,1-dimethylethyl)-4-iodophenol,M 12285 : 6-chloro-2,3-dihydro-1-(1-ocopropyl)-4(H)- quinolinone 4-oxime.

49. Miscellaneous Site 2 Diuretics:

50. Site 4 Diuretics : Potassium-Sparing Diuretics ■ A negative feature of all of the above-discussed classes of diuretics in current use is that they increase the renal excretion rate of K+ and thus can induce hypokalemia. ■ Over the years, three chemically distinct diuretics have emerged that increase Na+ and Cl- excretion without a concomitant increase in the urinary excretion rate of K+ . These agents are known as Potassium-Sparing diuretics or antikaliuretic agents. ■ The Potassium Sparing diuretics include: Spironolactone (a spirolactone), Triamterene (2,4,7-triamino-6-arylpteridine), and Amiloride (pyrazinoyl -guanidine). Sparing: استبقاء - حفظ