The Story of LIPITOR - A Peek into the World of - Chemistry

104 Pages·2007·1.42 MB·English

®
The Story of LIPITOR - A Peek into the World
of Pharmaceutical Process Chemistry
Ca2+
Chemical Synthesis
HO
CO
2
HO
F LIPITOR® – $12 billion/year sales (2005)
N
Chiral side chain (circled) – 220 ton/year
NH
O
2
Biocatalysis
Atorvastatin calcium
LIPITOR®
Aman Desai
7th Feb. 2007
The Problem – The “Bad” Cholesterol
• Cholesterol – a very important biological molecule.
• Most cholesterol is not dietary, it is
H
synthesized internally.
H H
HO
• Cholesterol is bound to lipoproteins and transported
Cholesterol
through blood.
High Density Lipoprotein (HDL) – “good”
• 2 kinds of lipoproteins
Low Density Lipoprotein (LDL) – “bad”
atherosclerosis
coronary heart disease & other cardiovascular diseases
One of the leading causes of death in the world today!
www.wikipedia.org
www.americanheart.org
The Solution – Suppressing Cholesterol Biosynthesis
OH O
O O O
HMG-CoA-Synthetase
+ SCoA
SCoA SCoA
O O
HSCoA HMG-CoA
2 NADPH + 2H+
Rate
HMG-CoA-Reductase
Limiting
2 NADP+ + HSCoA Step
OH OH
H H
H H
O O
HO
>25 steps Mevalonic Acid
Cholesterol
http://www.med.unibs.it/~marchesi/cholest.html
The Solution – Suppressing Cholesterol Biosynthesis
HO O OH O
HO O
O
SCoA
O O
O
2''
O O
O
H
O HMG-CoA
H
9'
9' 2 NADPH + 2H+
Lovastatin (MEVACOR®) Rate
HMG-CoA-Reductase
Mevastatin
Limiting
MERCK
2 NADP+ + HSCoA Step
Inhibition
HO
CO Na HO O
2
HO
O O
O
2''
O OH OH
H O
H
9'
HO O O
Pravastatin (PRAVACOL®) ®
Simvastatin (ZOCOR ) Mevalonic Acid
BRISTOL - MYERS SQUIBB
MERCK
Endo, A. J. Lipid Res. 1992, 33, 1569-1582.
Roth, B. D. Prog. Med. Chem. 2002, 40, 1-22.
Mechanism of Action of Statin Drugs
HO O
HO O
HO O O
O
O O O
O
O
SCoA
O H
H HMG-CoA
2 NADPH + 2H+
Rate
HMG-CoA-Reductase
Lovastatin (MEVACOR®) Limiting
Mevastatin
2 NADP+ + HSCoA Step
MERCK
Inhibition
O
HO ONa
HO O
OH
O O
O
OH OH
O
H O
H
O O
HO
Mevalonic Acid
®
Pravastatin (PRAVACOL ) ®
Simvastatin (ZOCOR )
BRISTOL - MYERS SQUIBB
MERCK
http://www.med.unibs.it/~marchesi/cholest.html
Mechanism of Action of Statin Drugs
HO O
HO O
O
O O
O
O
O H O Ca2+
H HO O
2
OH
®
Lovastatin (MEVACOR )
Mevastatin F
MERCK N
O
NH
HO ONa
HO O
O
OH
O O
O
Atorvastatin calcium (LIPITOR®)
O
H O PFIZER
H
HO
®
Pravastatin (PRAVACOL ) ®
Simvastatin (ZOCOR )
BRISTOL - MYERS SQUIBB
MERCK
http://www.med.unibs.it/~marchesi/cholest.html
Human HMGR with Natural Substrates
HO O
O
O
SCoA
HMG-CoA
2 NADPH + 2H+
Rate
HMG-CoA-Reductase
Limiting
2 NADP+ + HSCoA Step
Inhibition
OH OH
O O
Mevalonic Acid
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.
Human HMGR with Natural Substrates
HO O
O
O
SCoA
HMG-CoA
O Ca2+
HO O
2
OH
F
N
NH
O
LIPITOR®
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.
HO O
Human HMGR with Natural Substrates O
O
S
HMG-CoA
CH
2
CH
2
H N
C O
CH
2
CH pantothenic
2
acid
H N
C O
H C OH
H C C CH
3 3
CH
2
O
R
R= 3'-phosphoadenosine
diphosphate
Ca2+
O
HO O
2
OH
F
N
NH
O
®
LIPITOR
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.
Human HMGR with LIPITOR®
O Ca2+
HO O
2
OH
F
N
NH
O
®
LIPITOR
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.