Anti-hypertensive agents 고혈압 치료제 Anti-hypertensive agents

Systolic and Diastolic BP(수축기, 확장기 혈압)

The factors for BP

What is Hypertension?

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

Simplified Renin-Angiotesin-Aldosteron System

The controlling System of Blood pressure

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

Action Site of Antihypertensive Agents

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

ACE Related Drugs and Side Effects

Simple Mechanism of ACE Related Drugs Increasing Blood pressure

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

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.

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

ACE Inhibitors

Ca+2 Blocker and Side Effects

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

Clinical application of Ca Channel Blocker(CCB)

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

Clinical Application of Antihypertensive Agents

Management of Hypertensive Patients

ACE Inhibitors & Angiotensin Receptor Blockers(ARB)

Renin and ACE

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

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

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

Structural similarity of carboxypeptidase and ACE

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

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

New designed ACE I

The Binding mode of captopril

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

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

ACE Inhibitors with Proline analog

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

ACE Inhibitors with Bicyclic Ring and Dicarboxylic acid

Phosphinate Analog as ACE Inh.

Bioactivation Mechanism of Fosinopril

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

Structral similarity of teprotide and Captopril

Tetrotide and Lisinopril Binding Mode

Angiotensin II Receptor Antagonist(Blocker) : ARB

S-8308(lead comp of Anagiotensin II antagonist)

Development of Losartan from S-8308

Binding Mode of Losartan to Angiotensin Receptor

Development of Eporsartan from S-8308

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

Common Structure of Angiotensin II antagonist

Development of ARB

Angiotesin II antagonist (Losartan analogues)

ACE I

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)

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

Retrosynthesis Captopril

Synthesis Captopril

Synthesis Captopril

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

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

Retrosynthesis Lisinopril

Synthesis Lisinopril

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)

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.

Retrosynthesis Enalapril maleate

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

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)

Retrosynthesis Ramipril

Synthesis Ramipril

기타 혈관확장제

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

Retrosynthesis

Synthesis Hydralazine

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

Synthesis Cyclandelate

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)

Retrosynthesis Dipyridamole

Synthesis Dipyridamole