cardiovascular (cv) drugs 09/01/2018 · cl s ticlopidine (ticlid®) sanofi, 1978 (france), 1991...

Cardiovascular (CV) DrugsRohan Merchant Baran Group Meeting09/01/2018

What are Cardiovascular Diseases (CVDs)?■ Diseases of the heart■ Vascular diseases of the brain■ Diseases of blood vessels.

1. CVDs due to atherosclerosis: ■ ischaemic heart disease or coronary artery disease (e.g. heart attack) ■ cerebrovascular disease (e.g. stroke) ■ diseases of the aorta and arteries, including hypertension and peripheral vascular disease

2. Other CVDs ■ congenital heart disease ■ rheumatic heart disease ■ cardiomyopathies ■ cardiac arrhythmias

Some Background

In Atherosclerosis, fatty material and cholesterol are deposited inside the lumen of medium- and large-sized blood vessels (arteries). These deposits (plaques) cause the inner surface of the blood vessels to become irregular and the lumen to become narrow, making it harder for blood to flow through. Blood vessels also become less pliable as a result. Eventually, the plaque can rupture, triggering the formation of a blood clot. If the blood clot develops in a coronary artery, it can cause a heart attack; if it develops in the brain, it can cause a stroke.

Behavioural Risk Factors: tobacco use, physical inactivity, unhealthy diet, alcohol abuseMetabolic Risk Factors:• Raised Blood Pressure (hypertension)• Raised Blood Sugar (diabetes)• Raised Blood Lipids (cholesterol) - Not included in todays presentation• Overweight and ObesityOther Risk Factors: income, education, age, genetic, psychological

Cardiomyopathy makes it harder for the heart to pump blood to the rest of your body. The main types of cardiomyopathy include dilated, hypertrophic (thickening of heart muscle) and restrictive cardiomyopathy. It can lead to heart failure, blood clots, valve problems and cardiac arrest.

Risk Factors: high blood pressure, tissue damage from heart attack, valve problems, obesity

Rheumatic heart disease is caused by damage to the heart muscle and heart valves from rheumatic fever, following a streptococcal pharyngitis/tonsillitis.

The heart valves can remain stretched and/or scarred, and normal blood flow through damaged valves is interrupted. Blood may flow backward through stretched valves that do not close properly, or may be blocked due to scarred valves not opening properly. When the heart is damaged in this way, the heart valves are unable to function adequately, and heart surgery may be required. Untreated, RHD causes heart failure and those affected are at risk of arrhythmias, stroke, endocarditis and complications of pregnancy.

Once the acute illness has gone away, patients need to take penicillin, or an equivalent antibiotic, for many years to prevent recurrences. This is a very important treatment because the risk of heart valve damage increases if rheumatic fever recurs.

Malformations of heart structures present at birth are known as congenital heart defects. They may be caused by: (i) a close blood relation between parents (consanguinity); (ii) maternal infections (e.g. rubella); (iii) maternal use of alcohol and drugs (e.g. warfarin); and (iv) poor maternal nutrition (e.g. deficiency of folic acid). In some cases the cause remains unknown. Examples of congenital heart disease include holes in the septum of the heart, abnormal valves and abnormalities in heart chambers. It is the most common birth defect and was present in 48.9 million people globally (2015).

Cardiac arrhythmias occur when the electrical impulses that coordinate your heartbeats don't work properly, causing your heart to beat too fast, too slow or irregularly. They are classified as tachycardia (resting heart rate > 100 beats/min) and bradycardia (resting heart rate < 60 beats/min).

Atrial fibrillation is one of the common tachyarrhythmias arising from the atria. It is characterized by predominantly uncoordinated atrial activation with consequent deterioration of mechanical function of the heart. Atrial fibrillation increases the risk of stroke fivefold. Once atrial fibrillation is diagnosed, drugs are given to control the heart rate and anticoagulants are given to prevent stroke.

It can be caused by coronary artery disease, high blood pressure, drugs, alcohol abuse, electrolyte imbalance, diabetes.

■ Biggest cause of deaths worldwide (17 million in 2008)■ 40–59 year olds: ca. 40% people with CVD■ 60–79 year olds: ca. 70% people with CVD■ 80% of CVD deaths due to stroke and heart attack

Major causes of deaths Distribution of CVD deathsGlobal atlas on cardiovascular disease prevention and control (WHO)http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/

https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709

https://www.rhdaustralia.org.au/what-rheumatic-heart-disease

https://www.mayoclinic.org/diseases-conditions/heart-arrhythmia/symptoms-causes/syc-20350668

Classes of CV Drugs Covered in this GM:■ Anticoagulants (blood thinners)■ Antiplatelet medications■ Cardiac glycosides■ Diuretics■ Beta blockers■ Calcium channel blockers■ Angiotensin-converting enzyme (ACE) inhibitors■ Angiotensin receptor blockersNot Covered in this GM: ■ Cholesterol lowering drugs■ CV devices

Antithrombotic drugs

10 most important risk factors for all deaths

(6%)

(13%)

(5%)


Anticoagulants: They're given to people at a high risk of getting clots, to reduce their chances of developing serious conditions such as strokes, heart attacks, deep vein thrombosis and, pulmonary embolism.

Selected Anticoagulants on the Market:

O

OH

Ph

Me

O

Owarfarin

1948: rat poison1954: approved for medical use

(most commonly prescribed, ca. 40% maket share)

Vitamin K anatagonists (VKAs)Administration: Oral or IV

OO

HOOH

OOdicoumarol (NP)

1941: first coumarin anticoagulant

O

Ophenindione

Approved in 1950s(rarely used)

OO

O

HO3SOOH

O

NHSO3HHO2C

OH

OSO3HO

heparinnatural gylcosaminoglycanUsed medically since 1937

Injected into veinmade from pig intestinesantithrombin III agonist

Avg MW 12-15 kDa1 unit of heparin (Howell unit) =

0.002 mg of protein

Novel Oral Anticoagulants (NOACs)Rapid onset and offset of action, no strong drug or food interactions, less frequent monitoring and re-dosing (1/day)

Direct Factor Xa Inhibitors (no antidote)

N

N

OO

NH

OO

O

SClrivaroxaban (Xarelto®)

Bayer/J&J, 2011 FDA AprrovalFirst oral direct Xa inhibitor$5.64 billion (2017 sales)

NMe2O

NH HN

OS

NMeN

O

O

NH

N Cl

edoxaban (Savasya®)Daiichi Sankyo, 2011 (Japan) 2015 (US)

NH

O

MeOO

HN

N Cl

NH

NMe2

betrixaban (Bevyxxa®)Portola, 2017 (US)

N

NNO

H2N

O

N

OMe

Oapixaban (Eliquis®)

Pfizer/BMS, 2012 (EU), 2014 (US)$4.87 billion (2017 sales)

N

NMe

HNO

N

N

NH2

OnhexO

EtO2CN

dabigatran etexilate (Pradaxa®)BI, 2008 (EU), 2010 (US)Direct thrombin inhibitor

Antithrombotic Drugs (anticoagulants and antiplatelet drugs)

How do they work and why are they different?

• Fibrin and platelets most important components of a thrombus (clot) • Fibrin is a protein that forms a mesh that traps red blood cells• Platelets, a type of blood cell, form clumps that add to the mass of the thrombus • Both fibrin and platelets stabilize the thrombus and prevent it from falling apart • Fibrin is the more important component of clots that form in veins• Platelets are the more important component of clots that form in arteries

Anticoagulants slow down clotting, thereby reducing fibrin formation and preventing clots from forming and growing. Antiplatelet agents prevent platelets from clumping and also prevent clots from forming and growing.

see GM:Natural products inspired

drug discovery (Chu, 2017)

Example for Anticoagulant Factor Xa (FXa) is essential in formation of thrombin, a key mediator of both fibrin formation and platelet activation. Inhibition of FXa interrupts both the intrinsic and extrinsic activation pathways of thrombin production. FXa together with FVa, calcium, and phospholipids, a prothrombinase complex is formed, which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin and activates platelets, eventually leading to the formation of thrombus or blood clots. This process involves signal amplification, with one molecule of FXa activating many molecules of prothrombin to thrombin. Therefore, inhibition of FXa may be more effective than inhibition of thrombin.

https://en.wikipedia.org/wiki/Coagulation


N

NNO

H2N

O

N

OMe

O

apixaban (Eliquis®)Pfizer/BMS, 2012 (EU), 2014 (US)

4.87 billion (2017 sales)FXa Ki = 0.08 nM

J. Med. Chem. 2007, 50, 5339

SA862, FXa Ki = 0.15 nMThrombin Ki = 2000 µM

Bioorg. Med. Chem. Lett. 2000, 10, 685highly basic benzamidine (poor oral bioavailibility)

H2N

HN

N O

HN

OCO2H

NOStarting Point (Screening)

FXa Ki = 38.5 µM

H2N

NH N O

MeO2C

O

HN

NH2

NH

FXa Ki = 94 nMThrombin Ki = 16 µM

Bioorg. Med. Chem. Lett. 1997, 7, 2813dibasic compound (poor adsorption & PK),

ester instability

FXa Ki = 0.52 nMThrombin Ki = 400 µM

Bioorg. Med. Chem. Lett. 1998, 8, 3143Bioorg. Med. Chem. Lett. 1999, 9, 1195

J. Med. Chem. 1999, 42, 2752J. Med. Chem. 1999, 42, 2760

H2N

NH N O

N

O

HN

H2NO2SNN

N

H2N

NH N O O

HN

H2NO2S

isoxazole overlayed with the pyrazle analog(allows for substitution at 3-position)

NH2

NN

CF3HN

O

F

SO2Me

DPC423, FXa Ki = 0.15 nMBioorg. Med. Chem. Lett. 2000, 10, 685

Phase Iamidine analog (30x more potent in vitro,

<5% oral bioavailibility)J. Med. Chem. 2001, 44, 566

•TFApKa ~8.8

pKa ~10.7razaxaban, FXa Ki = 0.19 nM

Phase II (Proof-of-concept trial)J. Med. Chem. 2003, 46, 4405J. Med. Chem. 2005, 48, 1729

(invivo hydrolysis to primary aniline)

NN

CF3HN

O

F

N

NO

H2N

improves selectivity,poor solubility, permeability

N

NMe2

less lipophilicheterocycle

Review of FXa Inhibitors:J. Med. Chem. 2010, 53, 6243

razaxaban and apixaban overlayed

NNN

O

OEtO

I

MeO

HNO

1. CuI, phen2. NH3

16%(2 steps)

MeO

NH2

MeO

NHN

90%

N

O

Name Rxn

NO I

+Cl

CO2Et

1. Et3N2. TFA

71%(2 steps)

NH2

I

1. 5-Br valeryl chloride2. KOtBu3. PCl54. Li2CO35. morpholine

10%(5 steps)

DX-9065a (Initial Benchmark)Selective FXa inhibitor (IC50 41 nM)

No thrombin inhibition (conc > 2000 µM)Daiichi Pharmaceutical Company

J. Med. Chem. 1994, 37, 1200

H2N

NH

CO2H

ON

Me

NH

Evolution of apixaban (Eliquis®) as direct factor Xa inhibitor

NaNO2, HCl;A, NaOAc,

EtOH

Me

O

ClOEt

O

A MedChem Route


Antiplatelet Drugs

Heart attack, chest pain (angina), strokes, transient ischemic attacks (little strokes)They are effective in the arterial circulation, where anticoagulants have little effect

CO2HOAc aspirin

1980– (for CV)

COX inhibitor (thromboxane A2 antagonist)CO2H

OAc

F3C

triflusal1981 (Spain)

Adenosine diphosphate (ADP) receptor inhibitors (P2Y12 antagonist)

N

SCl

ticlopidine (Ticlid®)Sanofi, 1978 (France), 1991 (US)first in class thienopyridine drug

N

SCl

O OMe

clopidogrel (Plavix®)Sanofi, 1998 (US)

$1.70 bllion (2017 sales)

N

SF

O

OAcPrasugrel (Effient®)Daiichi Sankyo/Eli Lilly

2009 (US)

HO OH

O N

NN

N

N

S

HN

Me

F

F

ticagrelor (Brilinta®)AstraZeneca, 2011 (US)

OH

O

HO OH

NO

N

N

N

S CF3

HNSMe

POOO

PO O

HHP

Cl Cl

HOOHO

cangrelor (Kengreal®)Medicines Company,

2015 (US)

NH

O

N NN

N

O

cilostazol (Pletaal®)Otsuka, 1999 (US)

phosphodiesterase inhibitor

O

H

H H

H

EtO2CHNO

Me

N

F

vorapaxar(Zontivity®)

Merck, 2014 (US)Protease-activated receptor-1 (PAR-1)

antagonist

O

NH

O OH

HN

S OO

tirofiban (Aggrastat®)Medicure Pharma,

2010 (US)GP IIb/IIIa inhibitors

HNNH

HN

HN

NH

OO O

OHO

O

S S

HN

H2N

OO

N

O

Me

eptifibatide (Integrilin®)Gylcoprotein (GP) IIb/IIIa inhibitors

NN

NN

N

NN

N OH

OHHO

HO

dipyridamole (Persantine®)adenosine reuptake inhibitor

HNNH2

HN

HO OH

O N

NN

N

N

S

HN

Me

F

F

ticagrelor (Brilinta®)AstraZeneca, 2011 (US)

orally bioavailable

OH

O

HO OH

NO

N

N

N

NH2

POOO

POO O

HHPHO

OHOATP (pIC50 = 3.5)

natural antagonist (starting point)

Synthesis of ticagrelor (Bioorg. Med. Chem. Lett. 2007, 17, 6013)

med chem

HO

OF

F

1. SOCl22. sultam

80%(2 steps)

N

OF

FS

MeMe

O O

1. CH2N2, Pd(OAc)22. LiOH

50%

HO2C F

F

1. ClCO2Et2. NaN33. toluene, Δ4. HCl5. L-tartaric acid62% (5 steps)

H2N F

F•tartaric acid

Name Rxn

A

OH

OAc

(Boc)2NNa,Pd(PPh3)4

92%

OH

N(Boc)2

1. OsO42. HCl

96%(2 steps)

OH

NH2

HO

HO

1. DMP, H+2. CBzCl HO NHCBz

O O

Me Me

82%(2 steps)

ca. $125/g(Oakwood) 1. tBuOK,

BrCH2CH2OAc2. LiBH43. H2, Pd/C

85%(3 steps)

O NH2

O O

Me Me

HO

NNCl

SMe

H2N Cl

+DIPEA75%

O NH

O O

Me Me

N

NCl

H2N S

Me

HO

O N

O O

Me Me

NN

N N

Cl

S

OH

Me

1. A, DIPEA2. TFA

89%ticagrelor

(AZD6140)

isoamyl-nitrite 88%

triazolopyrimidine>100X fold

10x


O

H

H H

H

EtO2CHNO

Me

N

F

vorapaxar (Zontivity®)Merck, 2014 (US)Protease-activated receptor-1 (PAR-1)

antagonist

O

H

H H

H

O

Me

NMe

Me(+)-himbacine

investigated for Alzheimers11-step LLS total synthesis

(chemists at Schering-Plough)Natural Product PAR-1 inactive

J. Am. Chem. Soc. 1996, 118, 9812

(analogs from racemic

synthesis)O

H

H H

H

O

Me

N

Me

high-throughputscreening

(±) IC50 = 300 nM(+) IC50 = 150 nM (ent-NP)

(–) IC50 = 1500 nMJ. Med. Chem. 2005, 48, 5884

Me

OH

Me

OTHPMe

OH

CO2Bn

Me

OH

BnO2C

DHP, H+

100%

1. BuLi, BnCOCl2. TsOH

71%(2 steps)

Lindlar cat.,H2

93%

BrO

OO O 1. PPh3, Br22. (CH2OH)2, H+

O

O

61% (2 steps)

HO2COMe

O1. [Pd],

2. NaOH70% (2 steps)

+

DCC77%

O

OO

O

Me

BnO2C

xylene,215 ºC48%

O

O

HCO2Bn

O

O

Me

H

H

DBU99%O

O

HCO2Bn

O

O

Me

H

H

1. Pd/C, H22. PtO2, H2

O

O

HCO2H

O

O

Me

H

H

HSOCl2;

Bu3SnH, Pd(PPh3)4

48%O

O

HCHO

O

O

Me

H

H

H 1. HWE2. H+

O

H

O

O

Me

H

H

H

N

F

J. Med. Chem. 2007, 50, 129J. Med. Chem. 2008, 51, 3061

1. Ti(OiPr)4, NH32. NaBH3CN3. EtOCOCl

51%(3 steps)

vorapaxarUS and Canadian commercial rights acquired by Aralez Pharma in 2016

Beta Blockers

Medications for hypertension and to manage abnormal heart rhythms. They reduce blood pressure by blocking the effects of adrenaline. The heart beats more slowly and with less force, thereby reducing blood pressure. Additionaly, they also act as vasodilators.

While once a first-line treatment for hypertension, they are not as effective as diuretics, ACE inhibitors, or calcium channel blockers, and were downgraded in June 2006 to fourth-in-line (UK). Additionally, at usual doses they carry an unacceptable risk of provoking type 2 diabetes.

Banned by IOC (lower heart rate and reduce tremors) → used by surgeons

Beta receptors are found on cells of the heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues that are part of the sympathetic nervous system and lead to stress responses, especially when they are stimulated by adrenaline. Beta blockers interfere with the binding to the receptor of adrenaline and other stress hormones, and weaken the effects of stress hormones.

O

OHiPrHN

carvedilol(Coreg®)Roche, 1995 (US)

NH

OHO

NH

OMeO

propranolol (Inderal®)AZ, 1965 (US)

first commercial β-blockerdeveloper James Black won

1988 Nobel Prize in medicine

O

OHtBuHN

HO

HO

nadolol (Corgard®)

O O

HO

iPrHN

oxprenolol(Trasacor®)

OHO NHiPr

HN

pindolol (Visken®)Sandoz,1977 (US)

S NN

NO OH

O

timolol(Betimol®)1978 (US)

NHMs

HONHiPr

sotalol(Betapace®)

NH O

Me

OOH

NHiPrOnPr

acebutolol (Sectral®)

OOH

NHiPrO

H2Natenolol (Tenormin®)

1976 (UK)>20 β-Blockers Commercialized

NHtBu

NC NH2

O S2Cl2,DMF, rt40-60% N

SN

OHCl

NSN

OCl

HO NHtBu

timolol

HOOH

NHtBuA

from glyceradehyde

1. TsCl2. NaH, A

Synthesis of Timolol (Merck)

morpholine

J. Org. Chem. 1967, 32, 2823J. Org. Chem. 1976, 41, 3121


Calcium Channel Blockers (CCBs)

• Medications that disrupt the movement of calcium (Ca2+) through calcium channels.• Used as antihypertensive drugs• Particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients• Used to alter heart rate, to prevent cerebral vasospasm, and to reduce chest pain caused by angina pectoris (reduced blood flow to the heart)

• By acting on vascular smooth muscle, they reduce contraction of the arteries and cause an increase in arterial diameter, a phenomenon called vasodilation (CCBs do not work on venous smooth muscle)• By acting on cardiac muscles (myocardium), they reduce the force of contraction of the heart• By slowing down the conduction of electrical activity within the heart, they slow down the heart beat.• By blocking the calcium signal on adrenal cortex cells, they directly reduce aldosterone production, which correlates to lower blood pressure.

Hypertension, elevated blood pressure indicated by systolic or diastolic pressures exceeding 140 mmHg or 90 mmHg, respectively, is becoming an increasingly important medical problem as the general population becomes older and more overweight. A recent summary of research in the area of hypertension indicates that 50 million Americans and as many as one billion people globally suffer from hypertension (NHLBI, www.nhlbi.nih.gov, 2007). More importantly, the treatment of hypertension is becoming more complicated as the population ages, because many patients will take drugs to treat conditions such as diabetes, rheumatoid arthritis, atherosclerosis, and so on

NH

Me Me

MeO2C CO2MeNO2

nifedipine (Adalat®)Bayer, 1975 (US)

first commercial CCB

>15 dihydropyridineCCBs commercialized

NH

Me Me

MeO2C CO2EtCl

Cl

felodipine (Plendil®)AZ, 1988 (US)

(R) 1000x > (S) sold racemic

NH

Me

MeO2C CO2EtCl

O NH3

PhSO3

amlodipine besylate(Norvasc®)

Pfizer, 1988 (US)

CNMe

MeMeO

MeO

MeN OMe

OMeverpamil, 1981 (US)phenylalkylamine

N

S

O

OAc

OMe

diltiazem (Cardizem®)1982 (US)

benzothiazepine

N N

F

Fflunarizine(Sibelium®)

Ph

Me2N

In the body's tissues, the concentration of calcium ions (Ca2+) outside of cells is about 10000-fold higher than the concentration inside of cells. Embedded in the membrane of some cells are calcium channels. When these cells receive a certain signal, the channels open, letting calcium rush into the cell. The resulting increase in intracellular calcium has different effects in different types of cells. CCBs prevent or reduce the opening of these channels and thereby reduce these effects.

CCBs used as medications primarily have four effects:

Selected CCBs on the market

Commercial Synthesis of Diltiazem

SH

NH2O

RO2C

OMe

+toluene,

Δ

NH2

S

OH

OMe

CO2Rsteps,

chiral resolution

diltiazemUS4590188

(1986)(racemic)

SHNH2

OHNH4OH,

(NH4)2SO3,150 ºC

NH2

Ac2O,NaHCO3,

90 ºCNameRxn

76%(2 steps)

NHAc

S2Cl2,AcOH,80 ºC

NSS

ClNaHCO3,

rt

naphthothiazathiolium chloride

84%(2 steps)

NHSS

O

naphthodithiazole

NaOH,50 ºC90%

Route by Roche(Synthesis 1990, 6, 539)

A

Analogues at Roche

commercial

NameRxn

OMe

CHO

+

PhO

O

NaH,70 ºC

Name Rxn

PhO

O

O

OMe

54%,2:1 dr

desired pdtdirectly crystallizes

A, toluene,Δ; HCl

NH2

S OH

OMe

CO2R*

98%

1. NaOH2. H+, Δ

81%(2 steps)

HN

S

O

OH

OMe

>90% auxiliary recovered and reused

2 steps

Cl

Process Route by Roche(J. Org. Chem. 1992, 57, 851)

N

S

O

OAcMe2N

OMe

naltiazem(clinical candidate)more active analog

of diltiazem

OPhMgBr,

CuCl

(racemic)

Ph

OH

1. ClCH2COCl2. lipase Amano P-30 Ph

OH(–)84%

Ph

O+ O

Cl

auxiliary synthesis

Cardiovascular Diseases (CVDs)Rohan Merchant Baran Group Meeting09/01/2018

Angiotensin-Converting-Enzyme (ACE) Inhibitor

Treatment of hypertension, heart failure and after a heart attack (taken for life once started)

Relaxes blood vessels and decreases blood volume → lower pressure and decreased oxygen demand from the heart

• Inhibits ACE which is an important component of the renin-angiotensin system (hormone system that regulates blood pressure and fluid balance). • ACE catalyses the formation of angiotensin II from its precursor, angiotensin I• Angiotensin II is a powerful vasoconstrictor and increases blood pressure

N

O OHO

MeHS

captopril (Capoten®)BMS 1981 (US)

first ACE inhibitorthiol believed to cause rash and metallic taste

N

O OHOH

N

MeEtO

O

Ph

enalapril (Vasotec®)Merck, 1984 (US)Merck’s first billion dollar drug (1988)

N

O OHOH

N

MeEtO

O

Ph H H

ramipril (Altace®)Sanofi, 1991 (US)

N

OHN

MeEtO

O

Ph

quinapril (Accupril®)Pfizer, 1991 (US)

OHO

N

O OHOH

NHO

O

Ph

NH2

lisinopril (Zestril®)Merck/AZ, 1987 (US)

$1.2 billion (1999 sales)

HNEtO

O

Ph

NO

OH

O

benazepril (Lotensin®)Novartis, 1992 (US)

N

O OHOH

N

MeEtO

O

Ph H H

trandolapril (Mavik®)Abbott, 2006 (US)

NN

OOHO

HN

O

EtOPh

cilazapril (Inhibace®)Roche

N

O OHO

PO

OiPr

OEt

O

Phfosinopril (Monopril®)

BMS, 1991 (US)phosphinic acid Zn binding element

Cee, V.; Olhava, E. Leading ACE inhibitors for hypertensionThe Art of Drug Synthesis, 2007, Wiley & Sons

https://onlinelibrary.wiley.com/doi/pdf/10.1002/9780470134979.ch10

thiol ligand for active-site zinc ion and proline optimal C-terminal inhibitory residue

Pharmacological Paramters of ACE Inhibitors

Proposed binding of Ang I and early inhibitors to ACE

Br

H2NO

OMe

HO

+K2CO3 HN

OMeO

OH36% N

I

O

OMe

OBnO1. BnOCOCl2. I2, PPh3

41%(2 steps)

*

mixture of diastereomers(ratio not reported)

Bu3SnH,AIBN88%

NO

OMe

OBnO

H

HHN

O

OH

H

HN

O

OBn

OBnO

H

H Ti(OiPr)4,BnOH44%

diastereomersseparated 1.3:1 dr

H2,Pd/C91%

(1 step)

(7 step synthesis)

ramipril

Synthesis of Ramipril US5011940 (1987)

HN

OH

OO

Med Chem Route?1. MeOH, H+

2. NaBH4HN

OHO NO

OPhPhCHO,

pTsOH NOO

Ph

86%>20:1 dr 4

LDA

Br

>20:1 dr *

1. LAH2. H2, Pd/C

65% (3 steps)

HN

OHHN

O

OH

4

1. CbzCl2. Jones [O]3. H2, Pd/C

78% (3 steps)

J. Org. Chem. 1986, 51, 3140

Process RouteHN

OH

O

HO

1. BzCl2. MeOH, H+

3. MsOH, PPh3, DIAD, Et3N4. NaOH

HN

OH

O

MsO 84% (4 steps)

AlCl3,C6H6

BzN

OH

O

75%(100 kg) Bz cleavage &

hydrogenation

US4912231 (1990)Tetrahedron 1990, 31, 1241

Ph

50% H3PO2,AIBN, Δ

93%Ph

PO

OHH

CO2HClHMDS, TMSCl

82%Ph

PO

OHCO2H

Name RxnTet. Lett. 1984, 25, 4737

Org. Process Res. Dev. 1997, 1, 211Org. Process Res. Dev. 1997, 1, 315

fosinopril

Fosinopril Synthesis

Name Rxn


Angiotensin-Receptor Blockers (ARBs)

• AT1 receptors promote aldosterone secretion and Na retention by stimulation of angiotension receptors present on the adrenal cortex → elevated blood pressure due to vasoconstriction• AT2 receptors are present only in low levels and not associated with CV homeostasis.• The final step of the renin angiotensin cascade is the activation of angiotensin II receptors AT1 and AT2 by angiotensin II. • ACE inhibitors suppress RAS by blocking the formation of angiotensin II• Until 1995, ACE inhibitors only drugs capable of the RAS blockade (undesirable side effects such as a dry cough) • Angiotensin II AT1 receptor blockers more direct way to develop specific inhibitors of the RAS • Blocks the pathway more specifically than ACE inhibitors

NHNN

NN

NCl

HOnBu

losartan (Cozaar®)Merck, 1995 (US)

first ARB

NHNN

NN

O nBu

CO2H

Me

Mevalsartan (Diovan®)Novartis, 1997 US)

multi-billiondollar drugs

NHNN

NN

N O

nBu

irbesartan(Avapro®)

Sanofi/BMS,1998 (US)

[O] to acid by P450,

20x more active NnBu

CO2HS

HO2C •MsOH

eprosartan mesylate(Teveten®)

GSK, 1997 (US)

N

NnPr

Me

HO2CMeN

N telmisartan(Micardis®)

BI, 1999 (US)

NHNN

N1. Ph3CCl, Et3N2. nBuLi, B(OiPr)3; NH4Cl90% (2 steps)

NCPh3

NNN

(HO)2BH2N

CO2H

nBu OMe

NH+MeOH,

H2OnBu NH

NH

HO2CN

NH

nBuOHC

ClPOCl3,DMF55%

(2 steps)+

Br

Br

K2CO3

N

NnBuOHC

Cl

Br

NaBH490%

(2 steps)

N

NnBu

Cl

Br

HO

A

1. A, [Pd]2. H2SO4

88%(2 steps)

losartan

NameRxn

Merck Process Route for Losartan (J. Org. Chem. 1994, 59, 6391)

Me CNHCl,

MeOH NH

OMe72%

NH2

MeO2C

+NameRxn

93%Et3N

nBu

NH

NH

CO2Me

Br CHO

OH pTsOH,iPrOH

Br CHO

OiPr

A

A, K2CO3

N

N CHOnBu

MeO2C

Me

52%

SCO2H

EtO2C+

piperidine,110 ºC

N

NnBu

MeO2C

40%

CO2Et

S1. NaOH2. MsOH

70%(2 steps)

eprosartanmesylate

J. Med. Chem. 1992, 35, 3858J. Med. Chem. 1993, 36, 1880J. Org. Chem. 1997, 62, 8449

Perspective on Angiotensin-Receptor Blockers (ARB):

J. Med. Chem. 1996, 39, 625

NHNN

NN

N

OO

OEt

MeO

OO

candesartan cilexetil(Atacand®)

Takeda/AZ, 1998 (US)

Synthesis of Eprosartan Mesylate

NameRxn



Diuretics (Water Pills)

• Helps rid your body of salt (sodium) and water• Makes kidneys release more sodium into urine and sodium takes water with it from blood• Decreases the amount of fluid flowing through blood vessels, reducing pressure on vessel walls

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends that most people try thiazide diuretics first to treat high blood pressure and heart problems related to high blood pressure.

In addition, also prescribed for heart failure, liver failure, tissue swelling (edema) and certain kidney disorders, such as kidney stones

S NH

NCl

OOSH2N

O O

chlorothiazide (Diuril®)Merck, 1957 (US)first drug of class

Thiazide and thiazide-like diuretics (>10 commercialized)Inhibits the sodium-chloride symporter leading to retention of water in the urine. Frequent urination is due to the increased loss of water that has not been retained from the body as a result of a concomitant relationship with sodium loss from the convoluted tubule.

Cl

SH2N

O O HN

OH

Ochlortalidone (Hygroton®)

Novartis, 1960 (US)

S NH

HNCl

OOSH2N

O Odihydrochlorothiazide

(Apo-hydro®)

NH

ClSNH2O

O

O

NMe

indapamide

Loop diureticsInhibit the body's ability to reabsorb sodium at the ascending loop in the nephron, which leads to an excretion of water in the urine, whereas water normally follows sodium back into the extracellular fluid.

HN SNH2

OO

Cl

HO2C

O

furosemide (Lasix®)1962 (US)

HO2C S NH2

O O

OPhNHMe

bumetanide (Bumex®)

ClCl

OO

OH

OEt

ethacrynic acid (Edecrin®)

Potassium-sparing diureticsPotassium is retained and not as much is lost into the urine as with other diuretics.

N

NCl

H2N NH2

N

O

NH2

NH2

amiloride (Midamor®)

Merck, 1981 (US)

OMeO

H OMe

O

Me

O

H

Oeplerenone (Inspra®)Pfizer (Pharmacia),

2002 (US)

OMeO

HSAc

Me

O

H

H

H

spironolactone(Aldactone®) 1950s–

N

N

NN

Ph

NH2H2N

triamtrene(Dyrenium®)

Cl

NH2

ClSO3H,150 ºC Cl NH2

ClO2S SO2Cl

Cl NH2

H2NO2S SO2NH2

NH3 HCONH2 chloro-thiazide

N

N

Synthesis of Amyloride (Med-Chem Route)O

O

OHH2N

H2NOH

N

N OHN

NOH

OMe

NH2N

NO

1. NaOH2. MeOH, H+

1. SO2Cl22. NH3

63%(2 steps)

OMe

NH2N

NO

Cl

H2N

H2N

NH

NH2amylorideJ. Med. Chem. 1965, 8, 638J. Med. Chem. 1967, 10, 66

3,5-diaminouracil

eplerenone

Review on synthesis of other spironolactone derivatives

Steroids 2017, 118, 76

O

Me

H

H

H

O

OMe

O

Me

H

H

H

O

OMeAspergillus

ochraceus HO

canrenone

O

Me

H

H

H

O

OMeHO

Me Me

CNHO Et3N, LiCl

NC

NH2

O

Me

H

H

H

O

OMeHO

NC

O

HCl,H2O

O

Me

H

H

H

O

OMeHO

CO2Me

NaOMe,MeOH

1. MsCl2. HCO2K

O

Me H

H

O

OMe

CO2Me

H2O2,Cl3CN,

K2HPO4

7Other methods of installing C-7 Carbon by Pfizer:

Pd carbonylation (Synlett 2008, 418)Furan 1,6-addition/oxidative cleavage

to carboxylic acid (Org. Lett. 2006, 8, 2111)

Synthesis of Chlorothiazide (J. Am. Chem. Soc. 1957, 79, 2028)

Synthesis of Eplerenone WO1997021720A2 (Pharmacia)



Cardiac Glycosides

Family of compounds derived from the foxglove plant (Digitalis purpurea)

Increase the output force of the heart and decrease its rate of contractions by acting on the cellular sodium-potassium ATPase pump.

Treatments for congestive heart failure and cardiac arrhythmias Relative toxicity prevents them from being widely used.

sugar end of the steroid can alter the molecule’s solubility and kinetics

R

Osugar

general structure

OOR =

OO

bufadienolides(mainly TCM)

cardenolides

Me

OHH

HOHO

OH

H

O

OHOMe

HO

HOOH

OO

ouabain(Strodival®)

Me

OH

HMe

H

HOO

OHO

Me

OO

R

O

HOO

OMe

MeHO

HO

R = OH; digoxin (Lanoxin®) GSK, 1954 (US)R = H; digitoxin (Digitaline®)

According to GSK, farmers in the Netherlands grow fields of woolly foxglove, which is a member of the snapdragon family. Bales of dried foxglove leaves are shipped to the U.S. Here, processing facilities macerate the leaves and extract digitalis using an aqueous-alcohol solvent. Further treatment and processing yields powdered digoxin, which is compounded into tablets, injectable solutions, elixirs, and capsules. It takes about 1,000 kg of dried foxglove leaves to make 1 kg of pure digoxin, the company adds.

https://pubs.acs.org/cen/coverstory/83/8325/8325digoxin.html

‘The cardiac drug digoxin, in use for more than 200 years, stemmed from an herbal remedy rather than from laboratory chemistry. English physician William Withering is credited with discovering in 1775 that the foxglove plant could help those suffering from abnormal fluid buildup, or dropsy, as it was called in those days.

In a 1785 report, Withering writes that he was asked to evaluate a home remedy for dropsy compounded by Mrs. Hutton, "an old woman in Shropshire." Her herbal concoction "made cures after the more regular practitioners had failed," according to his report.

Withering, who was also a botanist, quickly figured out that of the 20 or so herbs in the woman's remedy, foxglove was the key ingredient. In his report, he noted that foxglove was particularly helpful for his patients who developed dropsy after suffering from scarlet fever or bad sore throats. Scarlet fever and strep throat, both caused by a Streptococcus bacterium, can damage the heart valves. Improperly functioning valves can lead to congestive heart failure--a condition in which fluid builds up in the body's tissues because of the heart's weak pumping action.Withering used dried foxglove leaves in his dropsy remedy. The leaves contain a number of glycosides--chemicals that are composed of a sugar and a cardenolide (which has a five-membered lactone ring)--that are called by the umbrella term digitalis. The flowers, seeds, and sap also contain digitalis, but less than the leaves have.’

Cl

ClO

N

CO2Htafamidis (Vyndaqel®)

Pfizer, 2011 (EU)familial amyloid cardiomyopathy

NH

O OH

O

Me

O

EtO NNH

NNN

CO2H

Me MeO

Me

sacbutril(neprilysin inhibtor)

valsartan(ARB)

Entresto® (sacbutril:valsartan 1:1)Novartis, 2015 (US)chronic heart failure

N

NPh

Ph N

Me Me

O NHMs

O

selexipag (Uptravi®)J&J, Nippon Shinyaku, 2015 (US)pulmonary arterial hypertension

prostacyclin receptor agonist

Other Drugs

losartanARBs(1995)

dabigartanNOAC(2008)

captoprilACE inhibitors

(1981)

nifedipineCCBs(1975)

popranololβ-blockers

(1965)

chlorothiazidediuretic(1957)

warfarinanticoagulant

digoxincardiac gylcoside

(1954)

ticlopidineantiplatelet

(1978)

What’sNext?

Projected Rise in Deaths from Different Diseases

cardiovascular (cv) drugs 09/01/2018 · cl s ticlopidine (ticlid®) sanofi, 1978 (france), 1991...

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