® 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.