1. Anti-hypertensive agents
고혈압 치료제
Anti-hypertensive agents

2. Systolic and Diastolic BP(수축기, 확장기 혈압)

3. The factors for BP

5. What is Hypertension?

6. Sympathetic-Renin-Angiotensin-Aldosterone System for Regulation of BP
b-blocker
a-blocker
Vasodilator
ACE Related
Renin Inh
Diuretics

7. Simplified Renin-Angiotesin-Aldosteron System

8. The controlling System of Blood pressure

9. Classification of Drugs for Hypertension
Renin 분비 억제
혈관 확장
심장 수축억제
심장 수축 억제
혈관 확장
혈액량 감소
Angiotensin II 생성 억제
혈관 확장
Angiotensin II 결합 억제

10. Action Site of Antihypertensive Agents

11. b-Blocker and Side Effects
Side Effects of b-blocker

13. ACE Related Drugs and Side Effects

14. Simple Mechanism of ACE Related Drugs
Increasing Blood pressure

16. Side Effects of ACEI
Increasing in bradykinin levels produced by ACE inhibitors
Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium
Rash and taste disturbances are more prevalent in captopril and is attributed to its sulfhydryl moiety. This has led to decreased use of captopril in clinical setting
ACE inhibitors might increase inflammation-related pain,perhaps mediated by the buildup of bradykinin that accompanies ACE inhibition

17. ACE I and Renal Failure
Renal impairment is a significant adverse effect of all ACE inhibitors, but the reason is still unknown. Some suggest it is associated with their effect on angiotensin II-mediated homeostatic functions, such as renal blood flow.
Renal blood flow may be affected by angiotensin II because it vasoconstricts the efferent arterioles of the glomeruli of the kidney, thereby increasing glomerular filtration rate (GFR). Hence, by reducing angiotensin II levels, ACE inhibitors may reduce GFR, a marker of renal function.
To be specific, they can induce or exacerbate renal impairment in patients with renal artery stenosis.
This is especially a problem if the patient is concomitantly taking an NSAID and a diuretic. When the three drugs are taken together, there is a very high risk of developing renal failure.

18. Triple Whammy Crisis
ACEI : efferent arteriole dilatation: reduce BP: decrease glomerular filtration rate (GFR)
NSAIDs: block prostaglandin production
: block afferent arteriole dilation: decrease glomerular perfusion
Diuretics : decrease the plasma volume : reduce renal plasma flow and BP
Improper Hypotension in Renal Blood Vessel and Severe Renal Failure crisis
Angiotensin II PG

19. ACE Inhibitors

21. Ca+2 Blocker and Side Effects

23. Ca+2 Blocker and Gingival hyperplasia
Some calcium channel blockers, including nifedipine, verapamil, diltiazem, and amlodipine, are well-documented with causing gingival hyperplasia.(6)                                                                                                                         
Ca+2 Blocker and Gingival hyperplasia
Some calcium channel blockers, including nifedipine, verapamil, diltiazem, and amlodipine, are well-documented with causing gingival hyperplasia

24. Clinical application of Ca Channel Blocker(CCB)

25. Diuretics
Some side effects of diuretics : dehydration due to potassium loss
gout for long time users
impotence in a small percentage of users.

26. Clinical Application of Antihypertensive Agents

29. Management of Hypertensive Patients

31. ACE Inhibitors & Angiotensin Receptor Blockers(ARB)

32. Renin and ACE

33. Proposed Binding of Angiotensin I to ACE
NH3+
CO2-
arginine
Glu

34. Enhance the d+ effect of C=O
Mechanism of ACE

35. Early ACE Inhibitors New ACE I Proline- arginine binding
적당한 위치의 C=O: Zn+2 binding

36. Structural similarity of carboxypeptidase and ACE

38. Structural similarity of D-2 benzylsuccinic acid succinic acid derivative as ACEI

39. Molecular design of ACEI
New ACE I
Succinic acid type
Free CO2H to bind NH3+
Proline moiety
Group to bind Zn+2

40. New designed ACE I

41. The Binding mode of captopril

42. Enalaprilat and Enalapril
Additional hydrophobic interaction
Very Polar : Poor absorption
Binding Mode of captopril and Enalaprilat
More affinity than captopril

43. Bioactivation of Enalapril
Two carboxylic acid : Too Polar to absorb through tissue : apply by IV not oral

44. ACE Inhibitors with Proline analog

45. Total Charge is neutral by intra molecular Di-Zwitterion form.
How About Lisinopril
Total Charge is neutral by intra molecular Di-Zwitterion form.

46. ACE Inhibitors with Bicyclic Ring and Dicarboxylic acid

47. Phosphinate Analog as ACE Inh.

48. Bioactivation Mechanism of Fosinopril

49. Teprotide ( Snake Poison) as ACE Inh.
Teprotide is nonapeptide which has been isolated from the snake Bothrops jararaca. It is an angiotensin converting enzyme inhibitor (ACE inhibitor), which inhibits the conversion of angiotensin I to angiotensin II and may potentiate some of the pharmacological actions of bradykinin. It has a molecular formula of C53H76N14O12 and has been looked at as an antihypertension agent

50. Structral similarity of teprotide and Captopril

51. Tetrotide and Lisinopril Binding Mode

53. Angiotensin II Receptor Antagonist(Blocker) : ARB

54. S-8308(lead comp of Anagiotensin II antagonist)

55. Development of Losartan from S-8308

56. Binding Mode of Losartan to Angiotensin Receptor

57. Development of Eporsartan from S-8308

58. How to design the Agonist and Antagonist of Receptor or Peptide Enzyme

59. Common Structure of Angiotensin II antagonist

60. Development of ARB

63. Angiotesin II antagonist (Losartan analogues)

64. ACE I

65. Captopril (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-L-proline
Capoten (Par Pharm), 캅토프릴 정(마이팜/삼진/영일), 아돌판 정(영풍), 에포스텐 정(뉴스카이팜), 카프릴 정(보령)

67. Clinical use
Captopril's main uses are based on its vasodilation and inhibition of some renal function activities.
1) Hypertension
2) Cardiac conditions such as congestive heart failure and after myocardial infarction
3) Preservation of kidney function in diabetic nephropathy
Limitations of captopril
The adverse drug reaction (ADR) profile of captopril is similar to other ACE inhibitors, with cough being the most common ADR.[12] However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the unique sulfhydryl moiety
Cough is the most common adverse effect. Hyperkalemia can occur, especially if used with other drugs which elevate potassium level in blood, such as potassium-sparing diuretics

68. Retrosynthesis
Captopril

69. Synthesis
Captopril

70. Synthesis
Captopril

71. Lisinopril
1-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-L-proline
Prinivil (Merck, 1987), 제스트릴 정(현대), 나노프릴 정 (진양),

72. Total Charge is neutral by intra molecular Di-Zwitterion form.
How About Lisinopril
Total Charge is neutral by intra molecular Di-Zwitterion form.

75. Retrosynthesis
Lisinopril

76. Synthesis
Lisinopril

77. Enalapril (S)-1-[N2-(1-carboxy-3-phenylpropy)-L-lysyl]-L-proline
Vasotec (Biovail Lab), 레니프릴 정 (중외), 에나프린 정 (종근당), 에이프릴 정 (유한메디카, 에카릴 정 (신풍), 엘라프릴 정 (한국파마)

78. This molecule was designed in order to move away from the sulfhydryl zinc-binding element of captopril,
which was believed to be responsible for captopril's short half-life and unfavorable side-effects.
Due to the poor oral absorption of enalaprilat, enalapril was designed as a monoester prodrug.
The ethyl ester facilitates absorption, and is hydrolyzed in the liver to enalaprilat, the active drug substance.
Esterification of the prolinyl carboxylate was also possible,
but stability of the drug substance was compromised due to diketopiperazine formation.

80. Retrosynthesis
Enalapril maleate

81. Synthesis Enalapril maleate Reductive alkylation
conventional method: NaBH3CN or NaBH(OAC)3
best condition for high diastereoselective for this transformation:
H2, Raney-Ni, KF, AcOH, EtOH, 3A MS

82. Ramipril
(2S,3aS,6aS)-1-((S)-2-((S)-1-ethoxy-1-oxo-4-phenylbutan-2-ylamino)propanoyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid
Altace(F) (King Pharms), 라미프린 정(태평양), 라미필 정(신풍), 트리테이스 정 (한독), 하트프릴 정(종근당)

84. Retrosynthesis
Ramipril

85. Synthesis
Ramipril

86. 기타 혈관확장제

87. Hydralazine 1-hydrazinylphthalazine
Apresoline (Novartis), 히드랄라진염산염 정/주(삼진), 안푸라솔 주 (세종)

88. Retrosynthesis

89. Synthesis
Hydralazine

90. Cyclandelate 3,3,5-trimethylcyclohexyl 2-hydroxy-2-phenylacetate
씨크란도 캅셀(일양)

91. Synthesis
Cyclandelate

92. Dipyridamole
2,2',2'',2'''-(4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diyl)bis(azanetriyl)tetraethanol
Persantine (Boeringer Ingelheim), 슈넬 펜톡시필린 주(슈넬)

93. Retrosynthesis
Dipyridamole

94. Synthesis
Dipyridamole