Antihypertensive Drugs.pptx

Antihypertensive Drugs

1. ANTIHYPERTENSIVE DRUGS Dr. Manoj R. Kumbhare Prof. Dr. M.R. Kumbhare

2. ANTIHYPERTENSIVE DRUGS Hypertension can be defined as the increase of arterial blood pressure above the limits. This chart reflects blood pressure categories defined by the American Heart Association . 3

3. ANTIHYPERTENSIVE DRUGS There are two types of hypertension: Most common type of hypertension (a) Primary (Essential) Hypertension (b) Secondary Hypertension ( 9 - 95 % ) Cause can not be identified Cause can be identified Such as renal hypertension (kidney diseases), Pheochromocytoma Prof. Dr. M.R. Kumbhare

4. Diuretics Centrally Acting Sympatholytics Adrenergic Neuron Blockers Adrenergic Receptor Blockers  -Adrenergic Receptor Blockers  1 -Adrenergic Receptor Blockers Direct Acting Vasodilators Potassium Channel Agonists Renin-Angiotensin System Inhibitors Calcium Channel Blockers Other Drugs CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS will be discussed in a separated section Prof. Dr. M.R. Kumbhare

5.  -ADRENERGIC BLOCKERS Activation of the   receptors in heart leads to an increase in rate and force of contraction.  -Receptor Blockers reduce the heart rate, contractility arterial pressure Depending upon these effects, these drugs reduce the work and the oxygen demand of heart and improve the oxygen supply /demand ratio. Prof. Dr. M.R. Kumbhare

6.  -ADRENERGIC BLOCKERS  -Receptor Blockers can be divided into two class depending on the receptor selectivity Nonselective  -Receptor Blockers (  1 and  2 blocking effect) (First Generation) Propranolol, timolol, nadolol, pindolol (some examples of this class)  1 -Selective Adrenergic Blockers (cardioselective  1 blockers) (Second Generation) Acebutolol, atenolol, metoprolol (some examples of this class) Nonselective  -Receptor Blockers with  1 antagonistic activity (Third Generation) labetalol,carvedilol Prof. Dr. M.R. Kumbhare

7.  -ADRENERGIC BLOCKERS  adrenergic receptor blockers are among the most widely used antihypertensive drugs and also considered for the first line treatment for glaucoma. Cardioselective    adrenergic receptor blockers have a greater affinity for the   - receptors in heart than for the   -receptors in other tissue. provides two important advantages (next slide please) Prof. Dr. M.R. Kumbhare

8.  -ADRENERGIC BLOCKERS Cardioselective    adrenergic receptor blockers have a greater affinity for the   - receptors in heart than for the   -receptors in other tissue. provide two important advantages   -Blockers do not have blocking effects on   -receptors on bronchi They can be used safely in patients with bronchitis or bronchial astma   -Blockers do not have blocking effects on vascular   -receptors mediating vasodilation Prof. Dr. M.R. Kumbhare

9.  -ADRENERGIC BLOCKERS  -Receptor Blockers are the derivatives of (a) Aryloxypropanolamine (mostly) or (b) Arylethanolamine Prof. Dr. M.R. Kumbhare

10. EXAMPLES OF  -ADRENERGIC BLOCKERS LABETALOL It is arylethanolamine type  -blockers. Labetalol is competetive nonselective  (  1 and  2 ) and  1 -receptor blocker. Labetalol is clinically useful antihypertensive agent. Prof. Dr. M.R. Kumbhare

11. EXAMPLES OF  -ADRENERGIC BLOCKERS LABETALOL Labetalol has two asymmetric centers (see the formula *). Two asymmetric centers correspond to 4 stereoisomers (RR, SS / RS, SR). Mixture of 4 stereoisomers is used in treating hypertension. However, the different isomers possess different receptor blocking activities (see nest slide) . Prof. Dr. M.R. Kumbhare * *

12. EXAMPLES OF  -ADRENERGIC BLOCKERS LABETALOL * * n: number of chiral centers 2 n : number of stereoisomers e n a n ti o m e r s n: 1 One chiral center 2 1 stereoisomers R E M I N D E R 2 enantiomers R n: 2 Two chiral center 2 2 stereoisomers 4 stereoisomers R, S S, R R, R S, S S e n a n ti o m e r s diastereoisomers Prof. Dr. M.R. Kumbhare

13. * * H O C H N O NH 2 EXAMPLES OF  -ADRENERGIC BLOCKERS LABETALOL OH CH 3 R R only  -blocker activity S R   -blocker activity S S   -blocker activity R S Possessing greater therapeutic activity Prof. Dr. M.R. Kumbhare

14. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM EXAMPLES OF  -ADRENERGIC BLOCKERS LABETALOL ethyl 2-hydroxybenzamide bu ty l Prof. Dr. M.R. Kumbhare (salicylamide) 2-Hydroxy-5-[1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl]benzamide

15. EXAMPLES  -ADRENERGIC BLOCKERS CARVEDILOL It is Aryloxypropanolamine type  -blockers. Carvedilol is competetive nonselective  (  1 and  2 ) and  1 -receptor blocker. It also has antioxidant and an antiproliferative effect on vascular smooth cells. Therefore, it possesses neuroprotective effect and ability H-carbazole-4-yloxy)-3-[2-(2- hoxyphenoxy)ethylamino]propan-2-ol 1 1 - ( 9 m e t carbazole to provide major cardiovascular organ protection Prof. Dr. M.R. Kumbhare * 4 3 1

16. EXAMPLES OF  -ADRENERGIC BLOCKERS CARVEDILOL Both enantiomers (R,S) have  1 -receptor blocking effects Only (S) enantiomer has  -blocking effect Carvedilol has one asymmetric center (see the formula *). One asymmetric center leads to 2 stereoisomers (enantiomers). Racemate is used in therapy. However, the enantiomers possess diferent receptor blocking activities . Prof. Dr. M.R. Kumbhare

17. CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS Diuretics Centrally Acting Sympatholytics Adrenergic Neuron Blockers Adrenergic Receptor Blockers  1 -Adrenergic Receptor Blockers  -Adrenergic Receptor Blockers Direct Acting Vasodilators Potassium Channel Agonists Renin-Angiotensin System Inhibitors Calcium Channel Blockers Other Drugs Prof. Dr. M.R. Kumbhare

18.  1 -ADRENERGIC RECEPTOR BLOCKERS Nonselective  -adrenergic receptor blockers are used in the treatment of catecholamine- dependent hypertension. These drugs , as non-specific –blocking agents, block both  1 and  2 adrenergic receptors. Blocking presynaptic  2 receptors leads to cardiac stimulatory effect and tachycardia. Examples of nonselective  adrenergic receptor blockers are Tolazoline, Phentolamine and Phenoxybenzamine. Prof. Dr. M.R. Kumbhare

19. Talozoline 2-benzyl-4,5-dihydro-1 H -imidazole N H N O H CH 3  1 -ADRENERGIC RECEPTOR BLOCKERS NONSELECTIVE  -ADRENERGIC RECEPTOR BLOCKERS N Phentolamine 3-[(4,5-dihydro-1 H -imidazol-2-yl) ( p -tolyl) amino]phenol used in persistent pulmonary hypertension of the newborn (has been used to treat Raynaud Syndrome) Prof. Dr. M.R. Kumbhare

20. N H N O H CH 3  1 -ADRENERGIC RECEPTOR BLOCKERS NONSELECTIVE  -ADRENERGIC RECEPTOR BLOCKERS N Phentolamine used to prevent or control hypertensive episodes in patient with pheochromocytoma a neuroendocrine tumor of the medulla of adrenal glands Prof. Dr. M.R. Kumbhare

21.  1 -ADRENERGIC RECEPTOR BLOCKERS NONSELECTIVE  -ADRENERGIC RECEPTOR BLOCKERS irreversible nonselective  -adrenergic blocker binds the receptors covalently 2-chloroethyl group alkylates the receptor Phenoxybenzamine N -benzyl- N -(2-chloroethyl)-1-phenoxypropan-2-amine Single dose of phenoxybenzamine may last 3 to 4 days. It is used in pheochromocytoma. Prof. Dr. M.R. Kumbhare

22.  1 -ADRENERGIC RECEPTOR BLOCKERS Selective  1 -adrenergic receptor blockers are used in the treatment of hypertension. produce antihpertensive effect by blocking the vasocontricting effect of  1 -adrenergic receptor on smooth muscle. These drugs do not have any effect on  2 -adrenergic receptors. Examples of selective    adrenergic receptor blockers are Prazosin, Terazosin and Doxasozin. Prof. Dr. M.R. Kumbhare

23.  1 -ADRENERGIC RECEPTOR BLOCKERS PRAZOSİN İupac: [4-(4-Amino-6,7-dimethoxyquinazolin- 2-yl)piperazin-1-yl]-(furan-2-yl)methanone N 3 N 1 Quinazoline Benzo[d]pyrimidine 4 7 2 5 6 8 piperazine 1 2 3 4 1 F u r a n 2 3 4 5 2-Furoic acid furan-2-carboxylic acid Prof. Dr. M.R. Kumbhare 4-Amino-2-[4-(2-furoyl)piperazin-1-yl]-6,7-dimethoxyquinazoline

24.  1 -ADRENERGIC RECEPTOR BLOCKERS SYNTHESIS OF PRAZOSİN Sodium cyanate (NaOCN) 2-amino-4,5-dimethoxybenzoic acid SOCl 2 Thionyl chloride Prof. Dr. M.R. Kumbhare

25.  1 -ADRENERGIC RECEPTOR BLOCKERS SYNTHESIS OF PRAZOSİN (continuing) NH 3 1-(2-furoyl)piperazine Prof. Dr. M.R. Kumbhare

26.  1 -ADRENERGIC RECEPTOR BLOCKERS PRAZOSİN Amino group at 4th position of quinazoline ring is very important for the  1 receptor affinity Prof. Dr. M.R. Kumbhare Prazosine is orally used as hydrochloride salt. Plasma half life is 2 to 3 hours. Side effects include dizziness, orthostatic hypotension (due to loss of reflex vasoconstriction upon standing).

27. DOXAZOSİN 2,3-dihydrobenzo[b][1,4]dioxine Amino group at 4th position of quinazoline ring 28 (2,3-dihydro-1,4-benzodioxin-3-yl)methanone Prof. Dr. M.R. Kumbhare is very important for the  1 receptor affinity. Saturated furan (tetrahydrofuran) [ 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-  1 -ADRENERGIC RECEPTOR BLOCKERS [4-(4-amino-6,7-dimethoxyquinazolin-2- yl)piperazin-1-yl]-(oxolan-2-yl)methanone TERAZOSİN

28. CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS Diuretics Centrally Acting Sympatholytics Adrenergic Neuron Blockers Adrenergic Receptor Blockers  1 -Adrenergic Receptor Blockers  -Adrenergic Receptor Blockers Direct Acting Vasodilators Potassium Channel Agonists Renin-Angiotensin System Inhibitors Calcium Channel Blockers Other Drugs Prof. Dr. M.R. Kumbhare

29. Adrenergic Neuron Blockers are comprised of two different groups: Reserpine and Derivatives Guanidine Derivatives Prof. Dr. M.R. Kumbhare ADRENERGİC NEURON BLOCKERS

30. ADRENERGİC NEURON BLOCKERS R E S E R P I N E Prof. Dr. M.R. Kumbhare Reserpine is an alkaloid isolated from the roots of Rauwolfia Serpentina. It affects the storage and release of norepinephrine. It depletes catecholamines and serotonine from central and peripheral neurons by interfering with the uptake of these amines. Reserpine is the first effective antihypertensive drug in western medicine. It has largely been replaced by newer agents with fewer side effects.

31. ADRENERGİC NEURON BLOCKERS R E S E R P I N E Prof. Dr. M.R. Kumbhare As indole derivatives, it is sensitive to decomposition by light and oxidation, especially in solution. Reserpine is used orally or parenterally for the treatment of hypertension.

32. ADRENERGİC NEURON BLOCKERS Guanethidine prevents the release of norepinepherine from the postganglionic neurons in response to sympathetic nerve stimulation and causes depletion of it in adrenergic neurons. İt is used orally for antihypertensive therapy. Prof. Dr. M.R. Kumbhare 2-[2-(azocan-1-yl)ethyl]guanidine G U A N E T H I D I N E Ocane: Suffixes for fully saturated eight membered ring without nitrogen

33. CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS Diuretics Centrally Acting Sympatholytics Adrenergic Neuron Blockers Adrenergic Receptor Blockers  1 -Adrenergic Receptor Blockers  -Adrenergic Receptor Blockers Direct Acting Vasodilators Potassium Channel Agonists Renin-Angiotensin System Inhibitors Calcium Channel Blockers Other Drugs Prof. Dr. M.R. Kumbhare

34. CENTRALLY ACTING SYMPATHOLYTIC DRUGS Centrally acting sympatholytic drugs are  2 -adrenergic receptor agonists. Prof. Dr. M.R. Kumbhare These drugs cause a decrease in sympathetic outflow from the central nervous system. Therefore, they decrease the peripheral vascular resistance, blood pressure and heart rate and contractility. Clonidine,  -methyldopa, guanabenz and guanafacine are examples of this class.

35. 1 H -Imidazole N H CENTRALLY ACTING SYMPATHOLYTIC DRUGS CLONIDINE Cl N H N C l 4 3 1 2 5 N H N H 2,3-dihydro-1 H -imidazole 4,5-dihydro-1 H -imidazole N H N H Imidazolidine REMINDER Indicated Hydrogen (2-imidazoline) (4-imidazoline) Prof. Dr. M.R. Kumbhare

36. 1 H -Imidazole 2,6-dichloro-N-(2-imidazolin-2-yl)aniline N H N CENTRALLY ACTING SYMPATHOLYTIC DRUGS CLONIDINE Cl 2-[(2,6-dichlorophenyl)amino]-2-imidazoline 4 3 1 2 5 N H N H 2,3-dihydro-1 H -imidazole 4,5-dihydro-1 H -imidazole N H Cl indicate the saturated positions indicate double bond’s position REMINDER (2-imidazoline) (4-imidazoline) Prof. Dr. M.R. Kumbhare

37. What is tautomerization ? Tautomerization is the process of isomerization of one tautomer into another tautomer. REMINDER Tautomers are two forms of the same compound which differ by positions of a hydrogen atom and a pi bond. The Equilibrium arrow is used to show the tautomer equlibrium. For example ketones and enols are tautomers: k e t on e e no l N H N H N C l C l N H H N N C l C l Clonidine tautomers can be drawn as follows Prof. Dr. M.R. Kumbhare

38. H 2 NCH 2 CH 2 NH 2 C l N C 3 H S C H N H Cl 2,6-dichlorophenyl- S -methylisothiourea -CH 3 SH -NH 3 N H N H N C l C l CENTRALLY ACTING SYMPATHOLYTIC DRUGS SYNTHESIS OF CLONIDINE C L O N I D I N E CH 2 CH 2 H H N H N H + Prof. Dr. M.R. Kumbhare

39. it exists to a significant extent in the nonionized form. The nonionized form can pass the membranes and / or BBB (Blood Brain Barrier). N H N H N CENTRALLY ACTING SYMPATHOLYTIC DRUGS CLONIDINE As a centrally acting drug, at physiological pH, Cl C l C l H N N N H C l G u a n i d i n e Prof. Dr. M.R. Kumbhare

40. As a centrally acting drug, at physiological pH, it exists to a significant extent in the nonionized form How can we explain this dilemma ? Guanidine (strong basic) (pKa=13.6) ionized at physiological pH Clonidine bears a guanidine moiety CENTRALLY ACTING SYMPATHOLYTIC DRUGS CLONIDINE Cl N H N N H C l Prof. Dr. M.R. Kumbhare

41. H N CENTRALLY ACTING SYMPATHOLYTIC DRUGS CLONIDINE As a centrally acting drug, at physiological pH, Cl it exists to a significant extent in the nonionized form. N N H Cl pKa of clonidine is much more lower than guanidine’s pKa. Guanidine (strong basic) ( p K a = 13 . 6 ) Clonidine (pKa= 8.0) Because of the inductive and resonanse effects of dichlorophenyl ring The basicity of clonidine is decreased 43

42. GUANABENZ 2-[(E)-(2,6-dichlorophenyl)methylideneamino]guanidine CENTRALLY ACTING SYMPATHOLYTIC DRUGS GUANFACINE N-( diaminomethylidene )-2-(2,6-dichlorophenyl)acetamide Prof. Dr. M.R. Kumbhare

43. G U A N A B E N Z GUANFACINE G u a n i d i n e C L O N I D I N E 20-25h C L O N I D I N E 17h G U A N F A C I N E 3h G U A N A B E N Z > > Elimination half-life is decreasing Prof. Dr. M.R. Kumbhare

44. H O H O CH 2 C O O H NH 2 C * H L - D O P A Dopa is the precursor of the catecholamines [dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline)]. Also used as antiparkinson drug. Flying wedge projection of L-Methyldopa L-Methyldopa has S configuration CENTRALLY ACTING SYMPATHOLYTIC DRUGS METHYLDOPA * ? Prof. Dr. M.R. Kumbhare

45. From IUPAC Gold Book D / L CONVENTION IN STEREOCHEMISTRY REMINDER An arbitrary convention according to which (+)-glyceraldehyde was named D- glyceraldehyde (with the enantiomer L-glyceraldehyde and its racemate DL- glyceraldehyde). Prof. Dr. M.R. Kumbhare D-glyceraldehyde (R)-2,3-dihydroxypropanal L-glyceraldehyde

46. REMINDER A chemical name is consisted of four parts in the IUPAC Nomenclature System IUPAC NOMENCLATURE PREFIX PARENT LOCANT SUFFIX indicate the location and identity of substituent(s) Defines the main part of the molecule and indicate the longest carbon chain or the ring, etc. identifies the primary functional group From Fundamental of Organic Chemistry by J. McMurry gives the location of the primary functional group Prof. Dr. M.R. Kumbhare

47. CENTRALLY ACTING SYMPATHOLYTIC DRUGS METHYLDOPA 1 2 3 4 3 1 2 propanoic acid 2-methyl 2-amino 3-(3,4-dihydroxyphenyl) * Substituents are written in alphabetical order P h e n y l a l a n i n e derivative 2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid Prof. Dr. M.R. Kumbhare

48. CENTRALLY ACTING SYMPATHOLYTIC DRUGS METHYLDOPA It is a prodrug. . Methyldopa is transported actively in the CNS by an aromatic acid transporter system. Then, it is converted to the metabolite responsible from the activity. This convertion is presented next slide. Prof. Dr. M.R. Kumbhare

49. CENTRALLY ACTING SYMPATHOLYTIC DRUGS CONVERSION OF METHYLDOPA TO ACTIVE METABOLITE AADC ( L -Aromatic Amino Acid Decarboxylase) M e t h y l d o p a  -Methyldopamine DBH (Dopamine-  -hydroxylase) (1R,2S)-  -Methylnorepinephrine active metabolite of methyldopa  2 -agonist Prof. Dr. M.R. Kumbhare

50. METHYLDOPA CENTRALLY ACTING SYMPATHOLYTIC DRUGS H O HO Methydopa is used only by oral route, because its zwitterionic character limits its solubility. Methyldopa absorption is limited and range 8% to 62%. Its absorption appears to involve an amino acid transport system . Therefore its absorption is affected by food and about 40% of absorbed drug is converted to O-sulfate conjugate by the intestinal mucosal cells. CH 2 NH 3 C C O O - CH 3 Prof. Dr. M.R. Kumbhare +

51. Methyldopa is unstable in the presence of oxidizing agents (also air), alkaline pH and light. METHYLDOPA CENTRALLY ACTING SYMPATHOLYTIC DRUGS H O H O CH 2 NH 3 C C O O - CH 3 Prof. Dr. M.R. Kumbhare + Catechol is very susceptible to oxidation

52. The ethyl ester of methyldopa is known as Methyldopate. The hydrochloride salt of methyldopate is highly water soluble and developed to make parenteral solution. Methyldopate is hydrolyzed to methydopa in the body by esterases. METHYLDOPA CENTRALLY ACTING SYMPATHOLYTIC DRUGS METHYLDOPATE Hydrochloride salt of METHYLDOPATE Prof. Dr. M.R. Kumbhare

53. CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS Diuretics Centrally Acting Sympatholytics Adrenergic Neuron Blockers Adrenergic Receptor Blockers  1 -Adrenergic Receptor Blockers  -Adrenergic Receptor Blockers Direct Acting Vasodilators Potassium Channel Agonists Renin-Angiotensin System Inhibitors Calcium Channel Blockers Other Drugs Prof. Dr. M.R. Kumbhare

54. DIRECT VASODILATORS These Drugs reduce arterial smooth muscle tone by direct action on the vasculature without interference from the autonomic innervation. They produce vasodilation and lower the blood tension. They can cause increase in heart rate and cardiac output by increased sympathetic reflex activity. Hydralazine, dihydralazine and sodium nitroprusside are the examples of this class. Prof. Dr. M.R. Kumbhare

55. DIRECT VASODILATORS HYDRALAZINE b e n z e n e a c b p y r i d a z i n e d 4 3 2 5 6 7 8 1 benzo[d]pyridazine p h t h a l a z i n e 1-hydrazinylphthalazine h y d r a z i n e Prof. Dr. M.R. Kumbhare

56. Synthesis of Hydralazine DIRECT VASODILATORS C C O H O 2-formylbenzoic acid OH PCl 5 phthalazin-1(2 H )-one Prof. Dr. M.R. Kumbhare phthalazin-1-ol - HCl - 2 H 2 O Added hydrogen

57. ADDED HYDROGEN IN NOMENCLATURE pyridin-2(1 H )-one 3 N 1 2 5 6 p y r i d i n e REMINDER ‘’Added Hydrogen’’ describes hydrogen atoms added to a specific structure as a consequence of the addition of a suffix or a prefix describing a structural modification. This type of indicated hydrogen is normally cited in parentheses after the locant of the additional feature. 4 4 3 2 5 6 N H N O 1 p y r i m i d i n e Prof. Dr. M.R. Kumbhare pyrimidin-2(1 H )-one From IUPAC Gold Book

58. HYDRALAZINE Hydralazine acts on vascular smooth muscle to cause relaxation. It is used orally as hydrochloride salt. Hydralazine is metabolized by microsomal enzymes and excreted by kidneys. Prof. Dr. M.R. Kumbhare DIRECT VASODILATORS

59. DIRECT VASODILATORS Metabolism of Hydralazine N N NHNH 2 O H Benzylic O x i d a t i o n Prof. Dr. M.R. Kumbhare A c e t y la t i o n Glucuronide Formation

60. D I H Y D R A L A Z I N E DIRECT VASODILATORS N NHNH 2 N NHNH 2 1,4-dihydrazinylphthalazine Prof. Dr. M.R. Kumbhare SODIUM NITROPRUSSIDE Na 2  Fe(CN) 5  NO Sodium nitroferricyanide This drug has short duration of action. Its use is limited to hypertensive emergencies. It forms nitric oxide (NO). The hypotensive effect of the drug is the result of nitric oxide.

61. CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS Diuretics Centrally Acting Sympatholytics Adrenergic Neuron Blockers Adrenergic Receptor Blockers  1 -Adrenergic Receptor Blockers  -Adrenergic Receptor Blockers Direct Acting Vasodilators Potassium Channel Agonists Renin-Angiotensin System Inhibitors Calcium Channel Blockers Other Drugs Prof. Dr. M.R. Kumbhare

62. POTASSIUM CHANNEL AGONISTS Prof. Dr. M.R. Kumbhare These drugs are also known as Potassium Channel Openers. These agents activate ATP-sensitive K + -channels in vascular smooth muscle. Opening potassium channels leads to a decrease of intracellular Ca +2 and results in hyperpolarization of the membrane. This process produces an inhibitory influence on the membrane excitation and causes vasodilation Minoxidil and diazoxide are the examples of this class.

63. 7-Chloro-3-methyl-2 H -1,2,4-benzothiadiazine 1,1-dioxide 2 H -1,2,4-thiadiazine 1,2,4-thiadiazine S 1 4 H N N 2 1 2 POTASSIUM CHANNEL AGONISTS 4 5 3 6 6 5 3 4 H -1,2,4-thiadiazine 1,2,4-thiadiazine benzo thiadiazine 2 H -1,2,4-benzothiadiazine 1 2 3 DIAZOXIDE 5 4 6 7 8 Indicated Hydrogen Prof. Dr. M.R. Kumbhare

64. POTASSIUM CHANNEL AGONISTS DIAZOXIDE Hydrochlorothiazide C h l o r o t hi a z i d e D i u r e ti c s İt was developed to increase the antihypertansive action and to minimize the diuretic effect (without sulfamoyl group!!) Acidic proton Sodium salt can be prepared Prof. Dr. M.R. Kumbhare

65. POTASSIUM CHANNEL AGONISTS DIAZOXIDE It is a rapidly acting antihypertensive agent for emergency reduction of blood pressure in hospitalized patient (with accelerated or malignant hypertension) by intravenous injection. Water soluble sodium salt is used for injectable formulation. Prof. Dr. M.R. Kumbhare

66. H 2 N NH 2 N 1 O 6 5 4 2 N 3 POTASSIUM CHANNEL AGONISTS M I N O X I D I L piperidine 2,6-diamino-4-(piperidin-1-yl)pyrimidine 1-oxide N pyrimidine N N N H 2 N NH 2 3 OSO - Minoxidil Sulfate Prodrug S u l f o tr a n s f e r a s e enzyme Active Metabolite Prof. Dr. M.R. Kumbhare (in the liver)

67. POTASSIUM CHANNEL AGONISTS MINOXIDIL N N N H 2 N NH 2 sodium and water retention, reflex tachycardia. Minoxidile is used for severe hypertension uncontrolled by other drugs. It is the only direct-acting vasodilator that requires metabolic activation to produce its antihypertensive effect. It has characteristic side effects of direct vasodilatory agents such as O Minoxidile topical solution is used to treat alopecia androgenitica . It is believed to increase cutaneous blood flow stimulating hair growth. Male-pattern baldness Prof. Dr. M.R. Kumbhare

68. POTASSIUM CHANNEL AGONISTS SYNTHESIS OF MINOXIDIL N N O H H O H O N N C l C l Cl 2,4,6--trichloropyrimidine POCl 3 NH 3 Barbituric acid m -chloroperbenzoic acid (MCPBA) 2,6-diamino-4-chloropyrimidine 1-oxide 2,6-diamino-4-chloropyrimidine Next Slide Please Prof. Dr. M.R. Kumbhare

69. POTASSIUM CHANNEL AGONISTS SYNTHESIS OF MINOXIDIL piperidine 2,6-diamino-4-chloropyrimidine 1-oxide N N N H 2 N NH 2 O Minoxidile N H - HCl Prof. Dr. M.R. Kumbhare

70. CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS Diuretics Centrally Acting Sympatholytics Adrenergic Neuron Blockers Adrenergic Receptor Blockers  1 -Adrenergic Receptor Blockers  -Adrenergic Receptor Blockers Direct Acting Vasodilators Potassium Channel Agonists Renin-Angiotensin System Inhibitors Calcium Channel Blockers Other Drugs Prof. Dr. M.R. Kumbhare

71. RENIN-ANGIOTENSIN SYSTEM INHIBITORS The renin-angiotensin hormonal system plays a central role in the control of sodium excretion and body fluid volume. It is closely connected with sympathetic system and aldosteron secretion in the regulation of blood pressure. Prof. Dr. M.R. Kumbhare

72. RENIN-ANGIOTENSIN SYSTEM INHIBITORS Sympathetic Stimulation Hypotension Decreased sodium extrection Angiotensinogen Angiotensin I K i dn e y s A glycoprotein Synthesized primarily in the liver Renin (an aspartyl protease) decapeptide Prof. Dr. M.R. Kumbhare

73. RENIN-ANGIOTENSIN SYSTEM INHIBITORS Angiotensin I Angiotensin II Angiotension Converting Enzyme A C E decapeptide Octapeptide a potent vasoconstrictor Significant regulatory effect on sodium excretion by renal tubes Prof. Dr. M.R. Kumbhare Glu-AP (Glutamyl aminopeptidase) Angiotensin III Less potent as vasoconstrictor

74. RENIN-ANGIOTENSIN SYSTEM INHIBITORS R e n i n Angiotensinogen Angiotensin I Angiotensin II Cardiac and Vascular Hypertrophy Systemic V a s o c o n t r i c t i on Increased Blood Volume Renal Sodium and Fluid Retention Aldosterone K i dn e y ELEVATED BLOOD PRESSURE Angiotension III A C E G l u - A P Prof. Dr. M.R. Kumbhare

75. RENIN-ANGIOTENSIN SYSTEM INHIBITORS R e n i n Angiotensinogen Angiotensin I Angiotensin II Cardiac and Vascular Hypertrophy Systemic V a s o c o n t r i c t i on Increased Blood Volume Renal Sodium and Fluid Retention Aldosterone K i dn e y ELEVATED BLOOD PRESSURE Angiotension III A C E G l u - A P Prof. Dr. M.R. Kumbhare

76. RENIN-ANGIOTENSIN SYSTEM INHIBITORS Renin-angiotensin system inhibitors can be classified as follows Angiotension Converting Enzyme (ACE) Inhibitors Angiotension Antagonists (Angiotension AT 1 Receptor Blockers) Renin Inhibitors Prof. Dr. M.R. Kumbhare

77. ACE INHIBITORS Prof. Dr. M.R. Kumbhare Captopril, Lisinopril , Enalapril, Benazepril, Quinapril, Ramipril, Fosinopril and Trandopril are the examples of Angiotension Converting Enzyme (ACE) Inhibitors. Enalapril, Benazepril, Quinapril, Ramipril, Fosinopril and Trandopril are prodrugs.

78. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM ACE INHIBITORS Prof. Dr. M.R. Kumbhare Because of the importance in regulating kidney function, aldosterone release, electrolyte balance and blood volume, the renin-angiotension system is very important drug target in the management of high blood pressure and hearth failure. They are used in hypertension and hearth failure A common side effect of ACE inhibitors is a dry cough appearing in about 10% of patients (it appears to be related to the elevation in bradykinin).

79. ACE INHIBITORS C A P T O P R I L * * ( S )-1-(( S )-3-mercapto-2-methylpropanoyl)pyrrolidine-2-carboxylic acid First ACE inhibitor used in therapy drugs (e.g. Penicillamine ) Sulfhydryl group is responsible for the excellent inhibitor activity It is also responsible two common side effects of captopril: Skin Rashes Taste disturbances (metallic taste, loss of taste) Prof. Dr. M.R. Kumbhare Common side effects of mercapto-containing

80. N C O H 2 C CH 3 H C S H C O O - A r g C H 2 N N + H H O H Zn ++ HYPOTHETICAL BINDING OF CAPTOPRIL IN THE ACTIVE SITE OF ACE Active site of ACE Arginine residue (cationic site) Zinc ion Hydrophobic pocket Hydrogen bond donor group P r o li n Prof. Dr. M.R. Kumbhare

81. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM David W. Cushman, Miguel A. Ondetti, Design of angiotensin converting enzyme inhibitors , Nature Medicine , Volume 5, Number 10, p.1110-1112, October 1999. Proposed binding to the active site of ACE by a substrate or venom peptide inhibitor with terminal sequence Phe–Ala–Pro, by succinylamino acids, and by captopril. Prof. Dr. M.R. Kumbhare

82. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM CONCLUSION The active site model that we described in our original studies used simple chemical concepts guided by a hypothetical ‘paper and pencil’ model of substrate and inhibitor binding to the enzyme. This rational design approach has led to a class of structurally simple compounds that can inhibit the action of the enzyme with great potency and specificity, properties that translate in vivo into effective antihypertensive activity with a remarkably low level of unwanted side effects or toxicity. 82 Prof. Dr. M.R. Kumbhare

83. ACE INHIBITORS L I S I N O P R I L * * * (S)-pyrrolidine-2-carboxylic acid (R)-6-aminohexanoyl (S)-1-carboxy-3-phenylpropyl CAPTOPRIL 83 Prof. Dr. M.R. Kumbhare

84. ACE INHIBITORS * 84 Prof. Dr. M.R. Kumbhare * * (S)-1-((R)-6-amino-2-((S)-1-carboxy-3-phenylpropyl)hexanoyl)pyrrolidine-2-carboxylic acid L I S I N O P R I L

85. PHARMACEUTICAL C EMU-SPRING TER ACE INHIBITORS SYNTHESIS OF CAPTOPRIL + DC C 3-(acetylthio)-2-methylpropanoic acid butyl pyrrolidine-2-carboxylate CF 3 COOH NH 3 butyl 1-(3-(acetylthio)-2-methylpropanoyl) pyrrolidine-2-carboxylate CAPTOPRIL N,N'-Dicyclohexylcarbodiimide 85 Prof. Dr. M.R. Kumbhare

86. ACE INHIBITOR PRODRUGS Enalapril, Benazepril, Quinapril, Ramipril, Fosinopril and Trandopril are examples of this class. Enalapril is the first and the prototype of this class. These drugs do not have thiol group (no common side effects!) Except fosinopril (containing phosphorus), all of them share the (S)-2-amino-4- phenylbutyric acid ethyl ester moiety. Why ester formation? (S)-ethyl 2-amino-4-phenylbutanoate 86 Prof. Dr. M.R. Kumbhare

87. General Structure of ACE Inhibitor Prodrugs ACE INHIBITOR PRODRUGS hydrolysis Metabolism by liver and intestinal enzymes Active metabolite 87 Prof. Dr. M.R. Kumbhare

88. ACE INHIBITOR PRODRUGS ENALAPRIL (S)-pyrrolidine-2-carboxylic acid * * * Propanoyl (propionyl) ((R)-1-ethoxycarbonyl-3-phenypropyl)amino C A P T O P R I L 88 Prof. Dr. M.R. Kumbhare

89. ACE INHIBITOR PRODRUGS ENALAPRIL Long-acting ACE inhibitor Maleate salt is used (S)-1-[(S)-2-[((R)-1-ethoxycarbonyl-3-phenypropyl)amino]propanoyl]pyrrolidine-2-carboxylic acid 89 Prof. Dr. M.R. Kumbhare

90. ACE INHIBITOR PRODRUGS ENALAPRIL h y d r o l y s i s in vivo 90 Prof. Dr. M.R. Kumbhare ENALAPRILAT Active Metabolite P r od r u g

91. ACE INHIBITOR PRODRUGS ENALAPRIL MALEATE Which nitrogen atom can be formed maleate salt ? Why? 91 Prof. Dr. M.R. Kumbhare

92. B E N A Z E P R I L H a N 1 H -azepine b 1 H -benzo[b]azepine 1 2 3 4 5 6 7 8 9 C 2 H 5 OOC 92 Prof. Dr. M.R. Kumbhare CH 2 H 2 C C N H H N O CH 2 COOH ACE INHIBITOR PRODRUGS 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl]acetic acid ((R)-1-ethoxycarbonyl-3-phenypropyl)amino

93. B E N A Z E P R I L C C 2 H 5 OOC CH 2 H 2 C N H H N O CH 2 COOH 2-[(S)-3-[((S)-1-ethoxycarbonyl-3-phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-1-yl]acetic acid ACE INHIBITOR PRODRUGS BENAZAPRILAT Active Metabolite 93 Prof. Dr. M.R. Kumbhare

94. Q U I N A P R I L ACE INHIBITOR PRODRUGS ((S)-1-ethoxycarbonyl-3-phenylpropyl)amino 1 (S)-propanoyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 94 Prof. Dr. M.R. Kumbhare

95. Q U I N A P R I L ACE INHIBITOR PRODRUGS (3S)-2-[(S)-2-[((S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propanoyl]-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid QUINAPRILATE Active Metabolite 95 Prof. Dr. M.R. Kumbhare

96. RENIN-ANGIOTENSIN SYSTEM INHIBITORS Renin-angiotensin system inhibitors can be classified as follows Angiotension Converting Enzyme (ACE) Inhibitors Angiotension Antagonists (Angiotension AT 1 Receptor Blockers) Renin Inhibitors 96 Prof. Dr. M.R. Kumbhare

97. A N G I O T E N S I N I I A N T A G O N I S T S 97 Prof. Dr. M.R. Kumbhare These drugs are the angiotension II receptor blockers. There are four subtypes of angiotension II receptors identified to date, namely AT 1 , AT 2 , AT 3 and AT 4 AT 1 receptors of angiotension II have importance in managing spesific cardiovascular diseases.

98. Stimulation of AT 1 receptors of angiotension II cause vasocontriction increased aldosterone synthesis and secretion increased vasopressin secretion decreased renal blood flow increased renal tubular sodium reuptake Other physiological events 98 Prof. Dr. M.R. Kumbhare A N G I O T E N S I N I I A N T A G O N I S T S

99. ANGIOTENSIN II ANTAGONISTS Competetive antagonists of AT 1 receptors of angiotension II produce vasodilatory effects. These drugs are used in the treatment of hypertension and heart failure in a similar manner as ACE inhibitors. Because they do not inhibit ACE, they do not cause an increase in bradykinin, which contributes to the some of the side effects of ACE inhibitors (cough and angioedema). Losartan, valsartan, candesartan, irbesartan and telmisartan are the examples of this class. 99 Prof. Dr. M.R. Kumbhare

100. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM General Structure for Losartan, Valsartan, Candesartan, Irbesartan and Telmisartan Prof. Dr. Erçin ERCİYAS, May 8, 2018 104

101. A N G I O T E N S I N I I A N T A G O N I S T S N HOH 2 C C 4 H 9 CH 2 N N N H N L O S A R T A N 101 Prof. Dr. M.R. Kumbhare 2-butyl-4-chloro-1-[4-[2-(1 H -tetrazol-5-yl)phenyl]benzyl]imidazole-5-methanole 1 2 N 3 Cl 4 5 Losartan is the first angiotension II AT 1 receptor antagonist Potassium salt is used orally. How?? From where can it give K salt? Brand name : Cozaar Tetrazole ring has acidic character and resembles the acidic function of angiotension II during receptor interaction.

102. A N G I O T E N S I N I I A N T A G O N I S T S N N HOH 2 C C 4 H 9 CH 2 N N N H N L O S A R T A N Cl Extensive first-pass metabolism N N C l C 4 H 9 CH 2 N N N H N H OOC This metabolite is closely 15 times more potent than the parent compound oxidation 102 Prof. Dr. M.R. Kumbhare

103. A N G I O T E N S I N I I A N T A G O N I S T S SYNTHESIS OF LOSARTAN NaOCH 3 N N HOH 2 C + 4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile (2-butyl-4-chloro-1 H -imidazol-5-yl)methanol C l C 4 H 9 CH 2 N C NaN 3 N N HOH 2 C C l C 4 H 9 CH 2 N N N H N 103 Prof. Dr. M.R. Kumbhare

104. A N G I O T E N S I N I I A N T A G O N I S T S VALSARTAN 2-[N-[4-[2-(1 H -tetrazol-5-yl)phenyl]benzyl]pentanamido]-3-methylbutanoic acid 104 Prof. Dr. M.R. Kumbhare

105. RENIN-ANGIOTENSIN SYSTEM INHIBITORS Renin-angiotensin system inhibitors can be classified as follows Angiotension Converting Enzyme (ACE) Inhibitors Angiotension Antagonists (Angiotension AT 1 Receptor Blockers) Renin Inhibitors 105 Prof. Dr. M.R. Kumbhare

106. RENIN INHIBITORS R e n i n Angiotensinogen Angiotensin I Angiotensin II Renin is a circulating enzyme secreted by kidneys in response to decreased glomerular filtration rate. Inhibitors of renin, by reducing the biosynthesis of angiotension II, have usefulness in managing cardiovascular diseases such as hypertension and heart failure . Renin inhibitors have been investigated more than 30 years; first member of this class, Aliskiren, has been introduced into therapy in 2007. Angiotension III A C E G l u - A P 106 Prof. Dr. M.R. Kumbhare

107. RENIN INHIBITORS ALISKIREN (5S,7S)- N -(3-amino-2,2-dimethyl-3-oxopropyl)-4,5-dihydroxy-2-isopropyl-7-(4-methoxy- 3-(3-methoxypropoxy)benzyl)-8-methylnonanamide It is the first renin inhibitor approved by FDA as hypertensive in 2007. 107 Prof. Dr. M.R. Kumbhare

108. CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS Diuretics Centrally Acting Sympatholytics Adrenergic Neuron Blockers Adrenergic Receptor Blockers  1 -Adrenergic Receptor Blockers  -Adrenergic Receptor Blockers Direct Acting Vasodilators Potassium Channel Agonists Renin-Angiotensin System Inhibitors Calcium Channel Blockers Other Drugs 108 Prof. Dr. M.R. Kumbhare

109. CALCIUM CHANNEL BLOCKERS Calcium Channel Blockers can be classified according to their chemical structures as follows: Benzothiazepine Derivatives Diltiazem Aralkylamine Derivatives (Diphenylalkylamine Derivatives) Verapamil 1,4-Dihydropyridine Derivatives Nifedipine, nicardipine amlodipine and others The effects of these three classes on myocardium and the arteries vary from one class to the other Prof. Dr. Erçin ERCİYAS, May 8, 2018 109 Prof. Dr. M.R. Kumbhare

110. CALCIUM CHANNEL BLOCKERS Benzothiazepines (diltiazem) and Aralkylamines (verapamil) affect both the hearth and arteriols Benzothiazepine Derivatives Diltiazem Aralkylamine Derivatives (Diphenylalkylamine Derivatives) Verapamil 1,4-Dihydropyridine Derivatives Nifedipine, nicardipine, amlodipine and others Therefore, benzothiazepines (diltiazem) and Aralkylamines (verapamil) are used clinically as antianginal, antiarrhythmic and antihypertensive 114 Prof. Dr. M.R. Kumbhare

111. CALCIUM CHANNEL BLOCKERS D i h y d r o p y r i d i n e s h a v e m u c h l e s s a f f e c t o n c a r d ia c ti ss u e s a n d h i g h e r specificity for the arteriols. Benzothiazepine Derivatives Diltiazem Aralkylamine Derivatives (Diphenylalkylamine Derivatives) Verapamil 1,4-Dihydropyridine Derivatives Nifedipine, nicardipine, amlodipine and others T h e r e f o r e , D i h y d r o p y r i d i n e s a r e u s e d f r e q u e n tl y a s a n ti a n g i n al a n d antihypertensive 111 Prof. Dr. M.R. Kumbhare

112. CLASS IV AGENTS (CALCIUM CHANNEL BLOCKERS) 112 Taken from antiarrhythmic drugs section

113. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM VERAPAMIL C L A SS I V 5-((3,4-Dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2- isopropyl pentanenitrile 113 Prof. Dr. M.R. Kumbhare

114. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM VERAPAMIL Verapamil works by relaxing the muscles of heart and blood vessels. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia. It has also been used as a vasodilator. 114 C L A SS I V Prof. Dr. M.R. Kumbhare

115. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM D I L T I A Z E M C L A SS I V 115

116. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM DILTIAZEM Diltiazem is used for treating: Heart pain (angina), High blood pressure, Abnormal heart rhythms. It is based upon a thiazepine ring. 116 C L A SS I V Prof. Dr. M.R. Kumbhare

117. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM B E P R I D I L C L A SS I V It has inhibitory effects on both the slow calcium and fast sodium inward currents in myocardial and vascular smooth muscle. 3 117 2 1 1 Prof. Dr. M.R. Kumbhare

118. MISCELLANEOUS TACHYARRHTHYMİC AGENTS

119. PHAR406 PHARMACEUTICAL CHEMISTRY IV EMU-SPRING TERM A D E N O S I N E MISCELLANEOUS 2 119 1 4 5 6 7 9 Prof. Dr. M.R. Kumbhare

120. R 1 R 2 R 3 CH CH NH OH R 5 BRADYCARDIA R 4 Compound R 1 R 2 R 3 R 4 R 5 Ephedrine 2-(methylamino)-1-phenylpropan-1-ol -H -H -H -CH 3 -CH 3 Isoproterenol (isoprenaline) -OH -OH -H -H - 1-(3,4-Dihydroxyphenyl)-2- isopropylaminoethanol CH(CH 3 ) 2 Metaproterenol (orciprenaline) -OH -H -OH -H - 1-(3,5-Dihydroxyphenyl)-2- isopropylaminoethanol CH(CH 3 ) 2 Terbutaline 1-(3,4-Dihydroxyphenyl)-2-tert- -OH -H -OH -H -C(CH 3 ) 3 butylaminoethanol 120 Prof. Dr. M.R. Kumbhare