Medicinal Chemistry of Diuretics PDF

Medicinal chemistry of diuretics By Takilu.A  Outline  Diuretics Carbonic anhydrase inhibitors High-ceiling or loop diuretics The thiazide and thiazide-like diuretics Potassium-sparing and other diuretics Introduction Diuretics are...

Medicinal chemistry of diuretics By Takilu.A  Outline  Diuretics Carbonic anhydrase inhibitors High-ceiling or loop diuretics The thiazide and thiazide-like diuretics Potassium-sparing and other diuretics Introduction Diuretics are agents that increase the rate of urine formation. – excretion of electrolytes and water from the body. Diuretics used in the treatment of edematous conditions and in the management of hypertension. Introduction The primary target organ for diuretics is the kidney, – where these drugs interfere with the reabsorption of sodium and other ions from the lumina of the nephrons. The amount of ions and accompanying water that are excreted as urine following administration of a diuretic is determined by many factors. Introduction Thus, it is important to be aware of the normal mechanisms of urine formation and renal control mechanisms – to understand clearly the ability of chemicals to induce diuresis. Normal Physiology of Urine Formation Two important functions of the kidney are – to maintain a homeostatic balance of electrolytes and water – to excrete water-soluble end products of metabolism. The kidney accomplishes these functions through the formation of urine by the nephrons  Urine formation initial steps 20% blood form GF Bicarbonate(80-90) NaCl by Na+/Cl− 50-60% of Na, Glucose and amino acids, phosphate (80-90%) 2-3% of Na ions Electrolytes and water Impermeable to water , but not ions (20% to 25% Na and Impermeable to ions, but not Cl) by (Na+/K+/2Cl−) water Structure Classif ication Current diuretics are classified by their – chemical class (thiazides), – mechanism of action (carbonic anhydrase inhibitors and osmotics), – site of action (loop diuretics), or – effects on urine contents (potassium- sparing diuretics) Cont’d… These drugs vary widely in their efficacy (i.e., their ability to increase the rate of urine formation) and their site of action within the nephron. Efficacy often is measured as the ability of the diuretic to increase the excretion of sodium ions filtered at the glomerulus Potency, which is the amount of the diuretic required to produce a specific diuretic response. Cont’d… Carbonic anhydrase inhibitors and potassium- sparing diuretics induce diuresis are weak diuretics??????????????? Diuretics: Sites and Mechanisms of Action Carbonic Anhydrase Inhibitors Carbonic Anhydrase Inhibitors  Polarity of the compound The first CAIs, thiadiazole derivative Specific a nd p er mit s a g r ea t er penetration into the ocular v Drugs f luid Sulfamoyl group is essential for CA inhibitory activity and for diuresis. SAR’s of CAI’s The free sulfamoyl nitrogen is important for diuretic activity. The mono- and di- substituents at SO 2 NH 2 abolish the activity. Substitution of the methyl group on one of the ring nitrogens (Methazolamide) retains the activity. The heterocyclic sulphonamides having highest lipid/water partition coefficient and lowest pKa values have greatest CA inhibitory and diuretic activity. The benzene meta sulphonamide derivatives have activity only when substituted with chlorine or methyl groups. Benzothiadiazine or Thiazide Diuretics Benzene disulfonamide derivatives – to find more efficacious carbonic anhydrase inhibitors. When the amino group was acylated, an unexpected ring closure took place. These compounds possessed a diuretic activity independent of the carbonic anhydrase inhibitory activity, and – a new series of diuretics called the benzothiadiazines was discovered. Cont’d… The major site of action of these compounds is in the distal convoluted tubule, – where these drugs compete for the chloride binding site of the Na / Cl– symporter and + inhibit the reabsorption of sodium and chloride ions.  Structure–Activity Relationship The thiazide diuretics are weakly acidic, with a benzothiadiazine1,1-dioxide nucleus. Additional point of  The most acidic b/c of sulfone group. acidity in the molecule  Alkyl substitution also decreases the polarity and increases the duration of diuretic action.  Structure–Activity Relationship These acidic protons make possible the formation of a water-soluble sodium salt that can be used for intravenous administration of the diuretics.   Dominant role in determining  The sulfamoyl group in the 7 position the potency and duration of is essential for diuretic effect. action of the thiazides.  Removal or replacement of this  Haloalkyl, aralkyl, or thioether group result in significant reduction substitution increases the lipid or complete loss of the diuretic activity solubility of the molecule. Saturation of the double bond to give a 3,4-dihydro derivative produces a diuretic that is 10-fold more active than the unsaturated derivative. An electron-withdrawing group is necessary for diuretic activity. Little diuretic activity is seen with a H atom Chloro or trif luoromethyl substitution are highly active. The trif luoromethyl-substituted diuretics Vs their chloro-substituted analogs When electron-releasing groups, such as methyl or methoxyl, are placed at position 6, the diuretic activity is markedly reduced. Specific examples Specific examples  High-Ceiling or Loop Diuretics This class of drugs is characterized more by its pharmacologic similarities than by its chemical similarities. Examples include furosemide, bumetanide, torsemide, and ethacrynic acid. These drugs produce a peak diuresis much greater than that observed with the other commonly used diuretics, hence the name high-ceiling diuretics.  Their main site of action is believed to be on the thick ascending limb of the loop of Henle, where they inhibit the luminal Na+/ K+/2Cl- symporter. These diuretics are commonly referred to as loop diuretics. Additional effects on the proximal and distal tubules also are possible. They are characterized by a quick onset (~30 min) and short duration (~ 6 hr) of action.  Specific Drugs-Furosemide Structure–Activity Relationships – Furosemide is an example of a high- ceiling diuretic and may be regarded as a derivative of anthranilic acid or o aminobenzoic acid.   The activating group (-X) in the 4 position can be Cl- or CF - 3  Phenoxy, alkoxy, anilino, benzyl or benzoyl groups substituted A sulfamoyl group in the 5 position at 4th position decreases is a prerequisite for optimal high- diuretic activity. ceiling diuretic activity. Substituent at the this position must be acidic  Furosemide has a saluretic effect 8- to 10- fold that of the thiazide diuretics; – however, it has a shorter duration of action (6 to 8 hours). Bumetanide This compound also functions as a high- ceiling diuretic in the ascending limb of the loop of Henle. It’s duration of action is approximately 4 hours.  For bumetanide, a phenoxy group has replaced the customary chloro or trifluoromethyl substitutions seen in other diuretic molecules. The phenoxy group is an electron-withdrawing group similar to the chloro or trifluoromethyl substitutions. The amine group customarily seen at position 6 has been moved to position 5. These minor variations from furosemide produced a compound with a mode of action similar to that of furosemide, but with a marked increase in diuretic potency.  The short duration of activity is similar, but the compound is approximately 50-fold more potent. Replacement of the phenoxy group at position 4 with a C6H5NH- or C6H5S- group also gives compounds with a favorable activity. However, when the butyl group on the C-5 amine is replaced with a furanylmethyl group, such as in furosemide, the results are not favorable. Ethacrynic acid Another major class of highceiling diuretics is the phenoxyacetic acid derivatives, of which ethacrynic acid is the prototypical agent. Structure–Activity Relationships Optimal diuretic activity was obtained – when an oxyacetic acid group was positioned para to an a, b-unsaturated carbonyl (or other sulfhydrylreactive group) and – chloro or methyl groups were placed at the 2- or 3- position of the phenyl ring. In addition, hydrogen atoms on the terminal alkene carbon also provided maximum reactivity.  Potassium Sparing Diuretics This class of diuretics are characterized by their ability  to increase Na+ and Cl- excretion without a concomitant increase in the urinary excretion rate of K+ in collecting duct. They are also known as antikaliuretic agents. They can be classified into 2 classes respect with mechanism of action: to 1. Aldosterone antagonists 2. Na+-channel blockers 1. Aldosterone antagonists Aldosterone enhances the passage of Na+ from the luminal fluid into tubular cells and the passage of intracellular K+ into the luminal f luid. A substance that antagonizes the effects of aldosterone could conceivably be a good diuretic. Spironolactone OH O CH2OH O O Aldosterone (Hemiacetal form) It is a competitive antagonist to the mineralocorticoids such as aldosterone on the minralocorticoid receptor. This lead to inhibition of reabsorption of Na+ and Cl- as well as the associated water. Particularly useful in primary aldosteronism (adrenal adenomas or hyperplasia) and in secondary aldosteronism (CHF, hepatic cirrhosis, ascites, nephrotic syndrome) – drug of choice in hepatic cirrhosis.  Adverse Effects of K+-Sparing Diuretics Hyperkalemia (contraindicated with renal insuf ficiency) Gynecomastia Hormonal disturbances due to its affinity for androgen and progestrone receptors. Metabolism O O COO O OH O O O O S Canrenone (Major Canrenoic acid anion O CH3 active metabolite) (Inactive metabolite) Eplerenone O O O O O CH3 O It is a recently approved specific aldosterone antagonist with a much lower affinity for androgen and progestrone receptors than spironolactone.  2. Na+-channel blockers Triamterene H 2N N N NH2 N N NH2 6-phenylpteridine-2,4,7-triamine It interferes with the process of cationic exchange by blocking luminal Na+-channel in the DCT. This lead to block the reabsorption Na+ and block the secretion of K+ without antagonizing the aldosterone. The main side effects are Kidney stones and leg cramps due to hyperkalemia. Amiloride Cl NH2 N HN H2N NH N O NH2 It is the open chain analog of triamterene acting with the same mode of action.