chemistry of cardiovascular drugs details, includes SAR, Mechanism, Structure, Uses, Formulations, Isolations etc.

1. jjj
Presented by: Souparnika T
Ist M.Pharm
Pharmaceutical Chemistry
CARDIOVASCULAR DRUGS
(LOVASTATIN,DICOUMEROL,TEPROTIDE)

2. CARDIOVASCULAR DRUGS
 The cardiovascular drug are the agent that affects the function
of the heart and blood vessel.
 The cardiovascular drug are used in the disorder such as
hypertension(high BP),Agina pectoris(chest pain resulting
from inadequate blood flow through the coronary
arteries to the heart muscles),Heart failure( inadequate output
of the heart muscle in relation to need of the rest of the body),
Arrythmia(disturbance of cardiac rhythm).
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3. TEPROTIDE - ACE INHIBITORS ( ANTIHYPERTENSIVE AGENTS)
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4. LOVASTATIN
• Lovastatin are the new generation drugs that were introduced into medicine for
treating hyperlipocholesterolemia, and they are unique compounds.
• Lovastatin is a cholesterol lowering agent that belong to class of medication called
statin.
• Discovered by Alfred alberts and his team at Merck in 1978.
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5. ISOLATION OF LOVASTATIN
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6. 6
CHEMISTRY OF LOVASTATIN
• Lovastatin,2-methylbutanoic acid 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-
(tetrahydro-4-hydroxy 6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester,
mevinolin,MK-803(mevacor)(formerly called mevinolin),is a potentinhibitor of
HMG-CoA.
• Molecular formula :C24H36O5
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7. 7
MECHANISM OF LOVASTATIN
Glucose
Glycolysis cycle
Pyruvate in Liver
Acetyl CoA enzyme
HMG-CoA Reductase
Statins
Mevalonic acid
Cholesterol
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8. 8
STRUCTURE ACTIVITY RELATIONSHIP
• Lovastatin are the lead compound in the development of HMG-CoA Reductases
inhibitors
 Lacton ring
 Bicyclic ring
 ethylene bridge are very essential for
the activity
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9. 9
• Pravastatin is the ring opened dihydroxy acid with a hydroxyl group, more
hydrophilic than lovastatin, making it less penetrating to be peripheral tissues and
hence less side effects.
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10. 10
Ring system
• The 3,5 dihydroxy carboxylate is essential for the inhibitory activity.
The compounds containing a lactone are prodrugs requirng in vivo hydrolysis
• A double bond between C and C can either increase or decrease the activity
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11. 11
• The ethyl group provides optimal activity for compounds containing
ring A and some heterocyclic rings.(eg.Pyrrole ring of Atorvastatin.)
• The ethenyl group is optimal for compounds with other rings
such as indole and pyrimidine rings seen in fluvastatin and
cerivastatin respectively
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12. 12
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13. 13
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 By modification of the methyl butyrl side chain
• The introduction of an additional methyl group to the carbonyl group -a compound with
2.5 times the intrinsic enzyme activity of lovastatin.
• A prodrug like Lovastatin, hydrolysed in liver to their active open chain dihydroxy acid
forms.
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15. • Compactin is a metabolite isolated from penicillium brevicompactin.it has antifungal
acivities and no action as an inhibitors of HMG-CoA Reductases
• PRAVASTATIN is the open hydroxy form of compactin.
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16. 16
• Decalin moeity of lovastatin replaced by fluorophenyl substituted heterocycles lead to the
discovery of statins such as Fluvastatin ,Cerivastatin,Atorvastatin.
. Highest LDL-CH lowering efficacy
. Additional anti-oxidant
• Withdrawn from the market in 2001 beacuse of the fatal
adverse drug-drug interaction.
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 Newer commonly used statin.
• Longer plasma half life
• Raises HDL-CH greater than other statins.
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18. USES
• Primary hyperlipidemia
• Myocardial infraction.
• Unstable angina
• Coronary revascularization proceudures.
CONTRAINDICATIONS
• Hypersensitivity and Active liver disease
• Pregnancy and lactation
WARNING
• Myopathy/Rhabdomyolysis
• Liver Dysfunction
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19. SOME MARKETED FORMULATION
• Atorvastatin-Storvas,Atorva,Aztor(10,20 mg tablet)
• Lovastatin -Rovacor,Lostatin,Lovacard(10,20,mg tab)
• Rosuvastatin- Rosuvas,Razel(5,10,20 mg tab)
• Simvastatin - Simvotin,Zocor,Simcard(5,10,20,mg tab)
• Pravastain-Pravator
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20. DICOUMAROL
• Dicoumarol or Dicumarol is a naturally occuring anticoagulant that functions as a
functional vitamin K depleter . It is also used in biochemical experiments as a inhibitor of
reductases.
• It is now known to be present in many other plants. Dicoumarol derivatives,Warfarin is
commonly used as a natural coagulant for the prevention and treatment of excessive
blood - clotting disorders.
O
O O
OH
O
OH
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21. ISOLATION OF DICOUMAROL
Dried whole or ground clover
NaOH (10 ml per g of clover)
The mixture was stirred for 30 min
Filtered into excess dilute HCI acid
Residual solid washed well with water
Acid solution was centrifuged.
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22. The solid obtained dried and extracted three times for 2 hr periods with boiling
chloroform 400ml
The combined chloroform extracts were reduced to 10ml and applied to a 40g column
of alumina
The column was eluted with chloroform (100ml)
The alumina was dried in vaccum and extracted with NaOH The basic solution was filterd
,acidified with conc.HCI,and extracted with chloroform
Evaporation of the chloroform gave dicoumarol,which was recrystallized from acetic
acid -water
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23. CHEMISTRY OF DICOUMAROL
• Dicoumarol is 3,3’- methylene-bis(4-hydroxycoumarin)
• Molecular formula :C19 H12 O6
• It is used as oral anticoagulant drug.
• It is metabolically produced from coumarin.
• As a functional vitamin K depletor.
• It also show pharmaceutical activities such as Anti-inflammatory,Antibacterial
,Antiviral,Anticancer etc.
O
O O
OH
O
OH
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24. MECHANISM OF ACTION
Dicoumarol is a competitative inhibitor of vitamin K epoxide reductase; thus it inhibits
vitamin K recycling and depletion of active vitamin K in blood . This prevents the
formation of the active form of prothrombin and several other coagulant enzymes,and
inhibits blood clotting.
Decarboxy prothrombin Prothrombin
Vitamin K hydroquinone Vitamin K epoxide
NAD NADH
(or f. VII,IX,X) (or f. VII,IX,X)
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25. STRUCTURE ACTIVITY RELATIONSHIP
• Dicoumarol or bishydroxycoumarin show slow and erratic onset of action. Thus synthetic
compounds with longer duration of action and fast onset of action were needed.
O
O O
OH
O
OH
Substitution decreases
anticoagulant effect
Both group is responsible for
specific interactions
Substitution increases
activity for ureases enzyme
inhibition
Important for anticoagulant activity
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26. • Warfarin - S(levorotatory) form is more potent than
R ( dextrorotatory) form. Showed increased duration of action.
Phenprocoumon Acenocoumarol---Rapid acting drug
• 4-Hydroxy coumarin residue substituted at the 3rd position
increases activity
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27. THERAPEUTIC USES
• Deep vein thrombosis,Oral anticoagulant
• Myocardiacal infraction and Cerebrovascular disease
CONTRAINDICATIONS
• Low vitamin K levels, Anaemia.
• Pregnancy etc
WARNINGS
• Hemorrhage.
FORMULATION
• Warfarin ----- Coumadin,Uniwarfin (1,2,3 mg tab)
• Coumarol------ Coumarol (50 mg tab)
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28. TEPROTIDE
• Teprotide is nonapeptide which has been isolated from the snake jararaca.
• The antihypertensive effects of teprotide were first obeserved by Swegio Ferrreira in 1965
• Teprotide was synthesized in 1970 and from there its antihypertensive properties were
studied more closely.
(Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro)
NH
O
O
N
H
N
N
H
O
NH
O
NH
N
H2
NH
N NH
O
N
H2 NH
O
NH N
CH3
CH3
O
O
O
OH
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29. CHEMISTRY OF TEPROTIDE
• Teprotide is nonapeptide which has been isolated from the snake Bothrops jararaca.
• It is an angiotensin converting enzyme inhibitors (ACE inhibitors)
• Molecular formula :C53H76N14O12
• IUPAC name : 5-oxo-L-pyrolyl-L-tryptophyl-L-prolyl-N5-(diaminomethylidene)-L-
ornithyl-L-prolyl-L-glutaminyl-L-isoleucyl-L-prolyl-L-proline
NH
O
O
N
H
N
N
H
O
NH
O
NH
N
H2
NH
N NH
O
N
H2 NH
O
NH N
CH3
CH3
O
O
O
OH
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30. ISOLATION AND DERIVED COMPOUND FROM TEPROTIDE
Isolated from the venom of
the brazillian viper
Bothrops jararaca
Screening of many N-acylated
peptide and SAR studies
1st generation of
ACE inhibitor
2nd generation of ACE
inhibitor
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31. DERIVED COMPOUNDS
CAPTOPRIL ENALAPRIL LISINOPRIL
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32. MECHANISM OF TEPROTIDE
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34. THERAPEUTIC USES OF TEPROTIDE
• Teprotide is first ACE inhibitor isolated from the venom of the snake Bothrops
jararaca.
• It is used to derived ACE Inhibitor drug such as captopril,enalopril.lisinopril,fosinipril
etc.
• It previously act as potent ACE inhibitors but nowdays it is not use as a ACE
inhibitors because it show less activity than captopril.
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35. REFERENCE
• KD Tripathi,Essentials of Medicinal Pharmacology, 7th edition ,jaypee brothers
Medical Publishers, Page no: 500-503,636-637
• Alfred Burger,Burger’s Medicinal Chemistry,Drug discovery and Development,
volume 1, Wiley, Sixth Edition, Page no 878-883
• Ferreira, Sergio (February 1965). "A bradykinin-potentiating factor (bpf) present in
the venom of bothrops jararaca". British Journal of Pharmacology. 24: 169–169.
PMC 1704050. PMID 14302350.
• Teprotide inhibits in a competitive manner the degradation of angiotensin I by the
converting enzyme, The Practice of Medicinal Chemistry (Second Edition), 2003
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36. • Image from google
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