The Story of LIPITOR ® - A Peek into the World of Pharmaceutical Process Chemistry Aman Desai 7 th Feb. 2007 Chemical Synthesis Biocatalysis LIPITOR ® – $12 billion/year sales (2005) Chiral side chain (circled) – 220 ton/year Atorvastatin calcium LIPITOR ® N CO 2 HO HO F O NH 2 Ca 2+
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The Story of LIPITOR® - A Peek into the World
of Pharmaceutical Process Chemistry
Aman Desai
7th Feb. 2007
Chemical Synthesis
Biocatalysis
LIPITOR® – $12 billion/year sales (2005)
Chiral side chain (circled) – 220 ton/year
Atorvastatin calciumLIPITOR®
N
CO2
HO
HO
F
O
NH
2
Ca2+
The Problem – The “Bad” Cholesterol
• Cholesterol – a very important biological molecule.
• Most cholesterol is not dietary, it is synthesized internally.
• Cholesterol is bound to lipoproteins and transported through blood.
• 2 kinds of lipoproteins
www.wikipedia.orgwww.americanheart.org
High Density Lipoprotein (HDL) – “good”
Low Density Lipoprotein (LDL) – “bad”
atherosclerosis
coronary heart disease & other cardiovascular diseases
One of the leading causes of death in the world today!
HOH
H
H
Cholesterol
The Solution – Suppressing Cholesterol Biosynthesis
http://www.med.unibs.it/~marchesi/cholest.html
O
SCoA
OHMG-CoA-Synthetase
SCoA
O
HSCoA
OH
SCoA
O
OO
HMG-CoA
2 NADPH + 2H+
2 NADP+ + HSCoA
HMG-CoA-Reductase
OH OH
OO
Mevalonic Acid
+
RateLimiting
Step
HHO
H
H
Cholesterol
H
>25 steps
The Solution – Suppressing Cholesterol Biosynthesis
OH
SCoA
O
OO
HMG-CoA
2 NADPH + 2H+
2 NADP+ + HSCoA
HMG-CoA-Reductase
OH OH
OO
Mevalonic Acid
RateLimiting
Step
Inhibition
Endo, A. J. Lipid Res. 1992, 33, 1569-1582.Roth, B. D. Prog. Med. Chem. 2002, 40, 1-22.
H
O
OHO
O
O
Lovastatin (MEVACOR®)MERCK
9'
2''
HO
O
HO
CO2Na
HO
HO
Pravastatin (PRAVACOL®)BRISTOL - MYERS SQUIBB
9'
H
O
OHO
O
O
Mevastatin
9'
H
O
OHO
O
O
Simvastatin (ZOCOR®)MERCK
2''
Mechanism of Action of Statin Drugs
O
HMG-CoA
2 NADPH + 2H+
2 NADP+ + HSCoA
HMG-CoA-Reductase
OH OH
OO
Mevalonic Acid
RateLimiting
Step
Inhibition
SCoA
HO O
O
H
O
OHO
O
O
Lovastatin (MEVACOR®)MERCK
HO
O
HO
Pravastatin (PRAVACOL®)BRISTOL - MYERS SQUIBB
ONaO
HO
OH
H
O
OHO
O
O
Mevastatin
H
O
OHO
O
O
Simvastatin (ZOCOR®)MERCK
http://www.med.unibs.it/~marchesi/cholest.html
Mechanism of Action of Statin Drugs
Atorvastatin calcium (LIPITOR®)PFIZER
NF
O
NH
2
Ca2+
OH
OO
HO
http://www.med.unibs.it/~marchesi/cholest.html
H
O
OHO
O
O
Lovastatin (MEVACOR®)MERCK
HO
O
HO
Pravastatin (PRAVACOL®)BRISTOL - MYERS SQUIBB
ONaO
HO
OH
H
O
OHO
O
O
Mevastatin
H
O
OHO
O
O
Simvastatin (ZOCOR®)MERCK
Human HMGR with Natural Substrates
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.
O
HMG-CoA
2 NADPH + 2H+
2 NADP+ + HSCoA
HMG-CoA-Reductase
OH OH
OO
Mevalonic Acid
RateLimiting
Step
Inhibition
SCoA
HO O
O
Human HMGR with Natural Substrates
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.
O
HMG-CoA
SCoA
HO O
LIPITOR®
NF
O
NH
2
Ca2+
OH
OO
HO
O
Human HMGR with Natural Substrates
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.
O
HMG-CoAS
OHO
O
CH2
CH2
NC OCH2
CH2
NC OC
H
H
OHHCH3C CH3
CH2
OR
R = 3'-phosphoadenosinediphosphate
LIPITOR®
NF
O
NH
2
Ca2+
OH
OO
HO
pantothenicacid
Human HMGR with LIPITOR®
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.
LIPITOR®
NF
O
NH
2
Ca2+
OH
OO
HO
Human HMGR with LIPITOR®
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.
LIPITOR®
NF
O
NH
2
Ca2+
OH
OO
HO
Circa 1995 – The Statin Drugs Market
Thayer, A. M. Chem. Eng. News, 2006, 84, 33, 26-27.Jones P.; Kafonek, S.; Laurora, I.; Hunninghake, D. Am. J. Cardiol. 1998, 81, 582-587.
• Merck = cholesterol control
• At 20 mg, ZOCOR® lowered LDL by -29%.H
O
OHO
O
O
Lovastatin (MEVACOR®)MERCK
H
O
OHO
O
O
Simvastatin (ZOCOR®)MERCK
Circa 1995 – The Statin Drugs Market
• Merck = cholesterol control.
• At 20 mg, ZOCOR® lowered LDL by -29%.H
O
OHO
O
O
Lovastatin (MEVACOR®)MERCK
H
O
OHO
O
O
Simvastatin (ZOCOR®)MERCK
Spring 1997 – Pfizer launches LIPITOR®!
• At 20 mg, LIPITOR® lowered LDL by -46%.
• 2005 – $12 billion sales, used by over 45 million people.
Atorvastatin calciumLIPITOR®
N
CO2
HO
HO
F
O
NH
2
Ca2+
The Story of LIPITOR® - a Peek into the World
of Pharmaceutical Process Chemistry
Chemical Synthesis
Biocatalysis
Drug Discovery
Process Development
Atorvastatin calciumLIPITOR®
N
CO2
HO
HO
F
O
NH
2
Ca2+
The Story of LIPITOR® - a Peek into the World
of Pharmaceutical Process Chemistry
Chemical Synthesis
Biocatalysis
Drug Discovery
Process Development
Atorvastatin calciumLIPITOR®
N
CO2
HO
HO
F
O
NH
2
Ca+2
Willard, A. K.; Novello, F. C.; Hoffmann, W. F.; Cragoe, E.; E. J. Jr. USP 4459422, 1984.Fortune, 2003, January 20.Roth, B. D. Prog. Med. Chem. 2002, 40, 1-22.Roth, B. D. et al. J. Med. Chem. 1990, 33, 21-31.
H
O
OHO
O
O
Mevastatin
H
O
OHO
O
O
Lovastatin (MEVACOR®)MERCK
HO
O
HO
CO2Na
HO
HO
Pravastatin (PRAVACOL®)BRISTOL - MYERS SQUIBB
?
?
The Decision of the Core TemplateThe Drug Discovery
F
O
OHO
MERCK
The Decision of the Core Template
H
O
OHO
O
O
Mevastatin
The Drug Discovery
Hydrolysis – 100-fold
loss in potency
Roth, B. D. et al. J. Med. Chem. 1990, 33, 21-31.
hydrophobic group
template
correct spatial relationship
A Potent HMGR Inhibitor
X
O
OHO
F
O
OHO
MERCK
Roth, B. D. et al. J. Med. Chem. 1990, 33, 21-31.
The Pyrrole TemplateThe Drug Discovery
N
X
R2R1
O
OHO
The Pyrrole TemplateThe Drug Discovery
Roth, B. D. et al. J. Med. Chem. 1990, 33, 21-31.
O+
O
FNEt3
S
N
HO
BnCl
58%
H2NCN
HOAc, reflux
73%N
CN
F
DIBAL-H92%
N
CHO
F
CH3COCH2CO2CH3
NaH, n-BuLiTHF, -78 °C
64%N
F
CO2CH3
O
HO
NF
CO2HHO
HO
1) Bu3B, NaBH4
THF, -78 °C2) NaOH, H2O2
toluene, reflux
52%tr ans:cis 97:3
NF
O
OHO
F O O
20 mol%
Roth, B. D. et al. J. Med. Chem. 1990, 33, 21-31.
The Pyrrole TemplateThe Drug Discovery
• Over 40 analogs prepared.
• Optimization studies for X, R1 and R2.
O+
O
FNEt3
S
N
HO
BnCl
58%
H2NCN
HOAc, reflux
73%N
CN
F
DIBAL-H92%
N
CHO
F
CH3COCH2CO2CH3
NaH, n-BuLiTHF, -78 °C
64%N
F
CO2CH3
O
HO
NF
CO2HHO
HO
1) Bu3B, NaBH4
THF, -78 °C2) NaOH, H2O2
toluene, reflux
52%tr ans:cis 97:3
N
X
R2R1
O
OHO
F O O
20 mol%
Roth, B. D. et al. J. Med. Chem. 1990, 33, 21-31.
The Need for Additional FunctionalityThe Drug Discovery
N
O
OHO
F
• IC50
(analog): 0.40 µM.
• Limit of current synthetic route.
H
O
OHO
O
O
MevastatinMERCK
IC50
– 0.030 µM.
The Need for Additional FunctionalityThe Drug Discovery
N
O
OHO
F
Roth, B. D. Prog. Med. Chem. 2002, 40, 1-22.
F
O
OHO
MERCK
F
O
OHO
An overlay
N
O
OHO
F
Roth, B. D. et al. J. Med. Chem. 1991, 34, 357-366.
Incorporation of Additional FunctionalityThe Drug Discovery
N
O
OHO
F
X X
X = ClX = Br
TBDMSClimidazole, DMF
25 ºC100%
N
O
OTBDMSO
F
1) 2 eq NCS or NBSDMF, 0 ºC100%
2) TBAF, HOAcTHF, 25 ºC35%
0.028Br
0.028Cl
0.23H
IC50
(µM)X
N
O
OHO
F
H
O
OHO
O
O
MevastatinMERCK
IC50
– 0.030 µM.
Incorporation of Additional FunctionalityThe Drug Discovery
N
O
OHO
F
X X
X = ClX = Br
TBDMSClimidazole, DMF
25 ºC100%
N
O
OTBDMSO
F
1) 2 eq NCS or NBSDMF, 0 ºC100%
2) TBAF, HOAcTHF, 25 ºC35%
N
O
OHO
F
Roth, B. D. Prog. Med. Chem. 2002, 40, 1-22.
Toxicity in early preclinical development! 0.028Br
0.028Cl
0.23H
IC50
(µM)X
H
O
OHO
O
O
MevastatinMERCK
IC50
– 0.030 µM.
Penta-substituted Pyrroles via [3+2]The Drug Discovery
Roth, B. D. et al. J. Med. Chem. 1991, 34, 357-366.
Br
CO2Et
F H2N O
O
NEt3, CH3CN, 25 ºC82%
NH
CO2Et
F
OO1) O
Cl
NEt3, CH2Cl2, 0 ºC
2) NaOH
N
HO2C
F
OO
O97%
O
NHPhPh
Ac2O, 90 ºC
NF
PhO
NHPh
OO1) HCl, EtOHreflux
2) p-TSA,acetone-waterreflux
N
CHO
F
PhO
NHPh
43%
87%
NF
PhO
NHPh
O
OHO
Penta-substituted Pyrroles via [3+2]The Drug Discovery
Roth, B. D. et al. J. Med. Chem. 1991, 34, 357-366.
NF
X Y
O
OHO
20 analogstested
NF
O
OHO
O
NH
(racemic)
IC50
– 0.025 µM
H
O
OHO
O
O
MevastatinMERCK
IC50
– 0.030 µM.
Penta-substituted Pyrroles via [3+2]The Drug Discovery
Roth, B. D. et al. J. Med. Chem. 1991, 34, 357-366.
NF
O
OHO
O
NH
(racemic)
resolution NF
O
OHO
O
NH
(R, R)
NF
X Y
O
OHO
20 analogstested
H
O
OHO
O
O
MevastatinMERCK
IC50
– 0.030 µM.
IC50
– 0.025 µM
(S, S) – 0.44
(R, R) – 0.007
IC50
(µM)
The Birth of LIPITOR®!The Drug Discovery
NF
O
OHO
O
NH
(racemic)
resolution NF
O
OHO
O
NH
(R, R)
Atorvastatin calciumLIPITOR®
N
CO2
HO
HO
F
O
NH
2
Ca2+
NF
X Y
O
OHO
20 analogstested
The Story of LIPITOR® - a Peek into the World
of Pharmaceutical Process Chemistry
Chemical Synthesis
Biocatalysis
Drug Discovery
Process Development
Atorvastatin calciumLIPITOR®
N
CO2
HO
HO
F
O
NH
2
Ca2+
The Story of LIPITOR® - a Peek into the World
of Pharmaceutical Process Chemistry
Chemical Synthesis
Biocatalysis
Drug Discovery
Process Development
Atorvastatin calciumLIPITOR®
N
CO2
HO
HO
F
O
NH
2
Ca2+
[3+2] Cycloaddition Route
N
HO2C
F
OO
O
O
NHPhPh1.6 eq
Ac2O, 90 ºC
43%
NF
PhO
NHPh
OO
Paal-Knorr Route: Penta-substituted
Pyrroles
Scale-up Issues and Potential SolutionsThe Process Development
Failed Model Study
Paal-Knorr Route: Tetra-substituted
Pyrroles
Roth, B. D. Prog. Med. Chem. 2002, 40, 1-22.
H2N
NF
OEt
OEtOEtEtO
F O O+
F
O
NH
O ONF
CO2RHO
HO
+
H2NCO2R
O O
NH
O
From Tetra- to Penta-substituted PyrrolesThe Process Development
Roth, B. D. et al. J. Med. Chem. 1991, 34, 357-366.Roth, B. D. Prog. Med. Chem. 2002, 40, 1-22.
Dr. Peter Seufer-Wasserthal (VP, Head of Codexis Pharma Services), personal communication.
• Excellent selectivities and yields.
• Purification only at the last step – reduced requirements.
• Green and safe.
• Reduced by-products.
• Mild reaction conditions.
• Efficient, scalable and cost effective.
• Commercialized: (1) Arch Pharmalabs, India – Codexis production partner.
(2) Lonza – a Pfizer supplier.
Cl
O
OEt
O
NC
O O
CO2tBu
1) KRED/GDH2) HHDH
3) Chemical chainelongation
4) KRED/GDH5) Protection
"TBIN"First crystalline intermediate
NC
OHOH O
OR
Biocatalytic Routes for the Chiral Side Chain
Thayer, A. M. Chem. Eng. News 2006, 84, (33), 26-27.Muller, M. Angew. Chem. Int. Ed. 2005, 44, 362-365.
NC
OHOH O
OR
OEt
OOH
Cl
HO OEt
OO OH
NCOH
OOH
NCOEt
OOH
O OHX
OH
OEt
OOCl
ADHGDH
Lipase
EtO OEt
OO OR1
NitrilaseCNNC
OH
1) ADH
2) Dehalo-genase
ClOEt
OO
AldolaseX
H
O+
H
O2
KANEKA
CIBA
DOWPHARMA(DIVERSA)
CODEXIS
DIVERSA
NC
OHOH O
OR
Biocatalytic Routes for the Chiral Side Chain
OEt
OOHCl
HO OEt
OO OH
NCOH
OOH
NCOEt
OOH
O OHX
OH
OEt
OO
Cl
ADHGDH
Lipase
EtO OEt
OO OR1
NitrilaseCNNC
OH
1) ADH
2) Dehalo-genase
ClOEt
OO
AldolaseX
H
O+
H
O2
NC
OHOH O
OR
NC
OHOH O
OR
KANEKA
CIBA
DOWPHARMA(DIVERSA)
CODEXIS
DIVERSA
Thayer, A. M. Chem. Eng. News 2006, 84, (33), 26-27.Muller, M. Angew. Chem. Int. Ed. 2005, 44, 362-365.
An Extremely Attractive Chemo-enzymatic Approach
NH2
CO2tBu
O
O
F
ONH
O O
LIPITOR®
N
CO2
HO
HO
F
O
NH
2
Ca2+
+
CHEMICALSYNTHESISat PFIZER
BIOCATALYSISat CODEXIS
Cl
O
O
O
CHEMICALSYNTHESISat PFIZER
O
NHPh
O
An Extremely Attractive Chemo-enzymatic Approach
NH2
CO2tBu
O
O
F
O
NH
O O
LIPITOR®
N
CO2
HO
HO
F
O
NH
2
Ca2+
+
CHEMICALSYNTHESISat PFIZER
BIOCATALYSISat CODEXIS
Cl
O
O
O
CHEMICALSYNTHESISat PFIZER
O
NHPh
O
Why not other pharmaceuticals and natural products also?
The Take-Home Message
The Story of LIPITOR®: Drug Discovery & Chemical Development
• The world of process chemistry works on the same basic principles as us here in this building.
• But in many respects, it is a vastly different world, driven by an entirely different set of considerations.
The Story of LIPITOR®: Biocatalytic Routes for the Sidechain
• State-of-art enzymatic transformations have reached an extraordinary level, making them valuable and competitive methods for use in the pharmaceutical industry.
• Biocatalysis has been emerging
The Take-Home Message
The Story of LIPITOR®: Drug Discovery & Chemical Development
• The world of process chemistry works on the same basic principles as us here in this building.
• But in many respects, it is a vastly different world, driven by an entirely different set of considerations.
The Story of LIPITOR®: Biocatalytic Routes for the Sidechain
• State-of-art enzymatic transformations have reached an extraordinary level, making them valuable and competitive methods for use in the pharmaceutical industry.
• Biocatalysis has been emerging clearly emerged as a very attractive tool in a synthetic chemist’s toolkit.
Acknowledgements
Dr. WulffDr. Walker Dr. Borhan Dr. Maleczka
Dr. Bruce Roth (VP, Global R&D, Pfizer)Dr. Donald Butler (Former Process Development Leader, Pfizer
Chief Science Advisor, Austin Chemical Company)Dr. Peter Seufer-Wasserthal (VP, Head of Pharma Services, Codexis)
Dr. Stephen Ritter (Senior Editor, C&EN)
Dr. Christopher Schmid (Lilly) Professor Samir ZardDr. Jos Brands (Merck) Dr. Michael Lipton (SPCorp)
Istvan, E. S.; Deisenhofer, J. Science 2001, 292, 1160-1164.Rosanoff, A.; Seelig, M. S. Journal of the American College of Nutrition 2004, 23, 501S-505.
• Promotion of new blood vessel growth.
• Stimulation of bone formation.
• Protection against modification of low density lipoproteins.
• Reduction of clot-forming process so important in plaque formation.
• Improvement in endothelial function.
• Reduction of inflammation in blood vessel tissue.
Some Rare Adverse Effects of Statin Drugs
www.lipitor.comRosanoff, A.; Seelig, M. S. Journal of the American College of Nutrition 2004, 23, 501S-505.
• The most common side effects are gas, constipation, stomach pain and heartburn.
• Rare Myalgia (muscle pain).
• Rare Rhabdomyolosis (skeletal muscle failure – loss of kidney function).
possibly life threatening!
Uncommon side reactions occur mainly when statins are co-prescribed with other
interacting drugs.
Statin Drugs
N
OO
HO
HO
H
O
OHO
O
O
Lovastatin (MEVACOR®)MERCK
H
O
OHO
O
O
Simvastatin (ZOCOR®)MERCK
HO
O
HO
C
HO
HO
Pravastatin (PRAVACOL®)BRISTOL - MYERS SQUIBB
Atorvastatin (LIPITOR®)PFIZER
N
CO2
HO
HO
F
O
NH
N
OO
HO
OH
F
Fluvastatin (LESCOL®)NOVARTIS
N
F
OO
HO
OH
O
Cerivastatin (LIPOBAY®)BAYCOL
withdrawn in 2001
N N
OO
HO
OH
N
F
SO
O
Rosuvastatin (CRESTOR®)ASTRAZENECA
F
Pitavastatin (LIVALO®)KOWA
O
O
Chemo-catalytic vs. Bio-catalytic: Wacker Specialty Chemicals