Bruce Roth Explained

Bruce D. Roth is an American organic and medicinal chemist who trained at Saint Joseph's College, Iowa State University and the University of Rochester, and, at the age of 32, discovered atorvastatin, the statin-class drug sold as Lipitor that would become the largest-selling drug in pharmaceutical history (as of 2003). His honours include being named a 2008 Hero of Chemistry by the American Chemical Society, and being chosen as the Perkin Medal awardee, the highest honour given in the U.S. chemical industry, by the Society of Chemical Industry, American section in 2013.

Early life and education

Roth received his undergraduate degree in chemistry from Saint Joseph's College, Philadelphia, in 1976.^[1] He then went to Iowa State University as a doctoral student under George Kraus, receiving his Ph.D. in organic chemistry in 1981.^[1] He then spent a year as a Postdoctoral Fellow with A.S. Kende at the University of Rochester.^[2]

Career

Roth has held a number of positions in his career, from "Scientist" (medicinal chemist) through to vice president-level positions in drug discovery, and his accomplishments in his career include the discovery of the molecule atorvastatin, which would become the drug Lipitor.

Positions

In 1982, 28-year-old Roth began work as a medicinal chemist for the Parke Davis research area of Warner-Lambert,^[2] becoming the chemistry co-chair of the statins effort, with biologist Roger Newton, in 1984.^[2] By 1985, he was at Warner-Lambert's Parke-Davis Pharmaceutical Research facility in Ann Arbor, Michigan. He was promoted to Research Associate in 1986, Senior Research Associate in 1988, Section Director in 1990, Director of Atherosclerosis and Exploratory Chemistry in 1992, and Senior Director of Atherosclerosis, Inflammation and Exploratory Chemistry in 1993.By the early 1990s he held managerial positions and was no longer doing laboratory work. In 2000 Warner-Lambert acquired Parke-Davis. He was appointed Vice President of Chemistry just prior to the merger between Warner-Lambert and Pfizer in 2000 and remained in that role as a part of Pfizer Global Research and Development in Ann Arbor, Michigan until 2007.^[3] He then joined Genentech in San Francisco, California as Vice President of Discovery Chemistry.^[4]

Atorvastatin

Before atorvastatin, Roth worked to develop a different drug, but Sandoz AG beat his team to a patent.^[5] In 1985, while working at Warner-Lambert's Parke-Davis research facility, Roth "identified a molecule" that inhibited HMG CoA reductase, a "key enzyme in the metabolic pathway the body uses to produce cholesterol."^[6]

Roth was listed as the inventor of trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one, patented in 1986, and developed into the on-market drug, atorvastatin, which ultimately would be sold as Lipitor,^{[2] [7] [8] [9]} and which would become the largest-selling drug in pharmaceutical history by 2003.^[10] Pfizer acquired Warner-Lambert and Lipitor in 2000.^{[10] [11] [12]}

Other activities

From 1996 until 2007, Roth served as an adjunct professor in the Department of Medicinal Chemistry at the University of Michigan.^[13]

Awards and honours

For the discovery of atorvastatin, Roth received the 1997 Warner-Lambert Chairman's Distinguished Scientific Achievement Award,^[3] the 1999 Inventor of the Year Award from the New York Intellectual Property Law Association, the 2003 American Chemical Society Award for Creative Invention,^[14] the 2003 Gustavus John Esselen Award for Chemistry in the Public Service,^[3] the 2005 Iowa State University Distinguished Alumni Award, and the 2006 Pfizer Global Research and Development Achievement Award. Roth was named a 2008 Hero of Chemistry by the American Chemical Society.^[15] In 2013, he was chosen as the Perkin Medal awardee, the highest honour given in the U.S. chemical industry, by the Society of Chemical Industry, American section, for his innovation in applied chemistry that resulted in the outstanding commercial success of atorvastatin.^[1]

Representative publications

According to the Chemical Heritage Foundation, in "addition to his discovery of atorvastatin, Roth is the inventor or co-inventor of 42 patents and the author or co-author of 48 manuscripts, 35 published abstracts and eight book chapters."^[16]

His publications include:

• Baumann, K.L. . Butler, D.E. . Deering, C.F. . Mennen, K.E. . Millar, A. . Nanninga, T.N. . Palmer, C.W. . Roth, B.D. . 3 . 1992 . The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase . . 33 . 17 . 2283–2284 . 10.1016/S0040-4039(00)74190-6.
• Brower PL, Butler DE, Deering CF, Le TV, Millar A, Nanninga TN, Roth BD . 1992 . The synthesis of (4R-Cis)-1, 1-dimethylethyl, 6-cyanomethyl-2,2-dimethyl-1,3- dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase . Tetrahedron Lett . 33 . 17. 2279–82 . 10.1016/s0040-4039(00)74189-x.
• Roth BD . Blankley CJ . Chucholowski AW . Ferguson E . Hoefle ML . Ortwine DF . Newton RS . Sekerke CS . Sliskovic DR . Stratton CD. etal. Jan 1991 . Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus . 10.1021/jm00105a056 . 1992137 . J Med Chem . 34 . 1. 357–66 .
• Roth BD . Bocan TM . Blankley CJ . Chucholowski AW . Creger PL . Creswell MW . Ferguson E . Newton RS . O'Brien P . Picard JA. etal. Jan 1991 . Relationship between tissue selectivity and lipophilicity for inhibitors of HMG-CoA reductase . J Med Chem . 34 . 1. 463–6 . 10.1021/jm00105a071. 1992149 .
• Shaw MK, Newton RS, Sliskovic DR, Roth BD, Ferguson E, Krause BR . Jul 1990 . Hep-G2 cells and primary rat hepatocytes differ in their response to inhibitors of HMG-CoA reductase . Biochem Biophys Res Commun . 170 . 2. 726–34 . 10.1016/0006-291x(90)92151-o. 2166504 .
• Roth BD, Ortwine DF, Hoefle ML, Stratton CD, Sliskovic DR, Wilson MW, Newton RS . Jan 1990 . Inhibitors of cholesterol biosynthesis. 1. trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a novel series of HMG-CoA reductase inhibitors. 1. Effects of structural modifications at the 2- and 5-positions of the pyrrole nucleus . J Med Chem . 33 . 1. 21–31 . 10.1021/jm00163a005. 2296019 .
• Sliskovic DR, Roth BD, Wilson MW, Hoefle ML, Newton RS . Jan 1990 . Inhibitors of cholesterol biosynthesis. 2. 1,3,5-trisubstituted [2-(tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles . J Med Chem . 33 . 1. 31–8 . 10.1021/jm00163a006. 2296027 .
• Roth BD, Bocan TMA, Blankley CJ, Chucholowski AW, Creger PL, Creswell MW, Ferguson E, Newton RS, O'Brien P, Picard JA, Roark WH, Sekerke CS, Sliskovic DR, Wilson MW. The Relationship Between Tissue Selectivity and Lipophilicity for Inhibitors of HMG-CoA Reductase. J. Med. Chem. 1991, 34, 463-6.
• Kende AS, Roth B, Sanfilippo PJ . 1982 . Facile, palladium (II)- mediated synthesis of bridged and spirocyclic bicycloalkenones . J Am Chem Soc . 104 . 6. 1784–5 . 10.1021/ja00370a076.
• Kende AS, Roth B, Sanfilippo PJ, Blacklock TJ . 1982 . Mechanism and regioisomeric control in palladium (II) - mediated cycloalkenylations. A novel total synthesis of (+/-)-quadrone . J Am Chem Soc . 104 . 21. 5808–10 . 10.1021/ja00385a053.
• Roth BD, Roark WH . 1988 . Synthesis of a chiral synthon for the lactone portion of compactin and mevinolin . Tetrahedron Lett . 29 . 11. 1255–8 . 10.1016/s0040-4039(00)80269-5.
• 2002 . The Discovery and Development of Atorvastatin, a Potent Novel Hypolipidemic Agent . . King, F.D. . Oxford, A.W. . Reitz, Allen B. . Dax, Scott L. . Roth, B.D. . 40 . 1–22 . 978-0-444-51054-9 . 12516521 . 10.1016/S0079-6468(08)70080-8.

Further reading

The following are good sources from which further information on the article's subject may be found, that may be of interest to readers and article editors. It includes sources not yet cited, and sources whose content may yet provide further insights into the subject.

• Book: Li, Jie Jack . 2006 . Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use . Cardiovascular Drugs: From Nitroglycerin to Lipitor (Chapter 3) . 75–102, esp. 100–102 . Oxford, ENG . . 978-0-19-534576-6 . https://books.google.com/books?isbn=0195345762 . 2 February 2016 .
• Petersen, Melody . 2000 . Pfizer Gets Its Deal to Buy Warner-Lambert for $90.2 Billion . . online, print . February 8 . 2 February 2016 .
• Roth, Bruce D. (2003) "Discovery and development of Lipitor (atorvastatin calcium)," ACS Award for Creative Invention Symposium: New Therapies for Atherosclerosis, MEDI 158 (March 24), The 225th ACS National Meeting, New Orleans, LA, March 23–27, 2003.

External links

• Ann Arbor chemist wins national award for drug discovery - ScienceBlog
• Bruce D. Roth, Pfizer Inc, USA

Notes and References

1. Knight, Jess . 2013 . ISU Chemistry Alum, and Current Graduate Student, Earn Perkin Medal Awards . online . News Release, College of Liberal Arts and Sciences, ISU . 5 September . 2 February 2016 .
2. Book: Li, Jie Jack . 2006 . Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use . Cardiovascular Drugs: From Nitroglycerin to Lipitor (Chapter 3) . 75–102, esp. 100–102 . Oxford, ENG . . 978-0-19-534576-6 . https://books.google.com/books?isbn=0195345762 . 2 February 2016 .
3. Book: Li, Jie Jack . 2009 . Triumph of the Heart: The Story of Statins . Cardiovascular Drugs: From Nitroglycerin to Lipitor (Chapter 3) . 98f . Oxford, ENG . . 978-0-19-804351-5 . https://books.google.com/books?isbn=0198043511 . 2 February 2016 .
4. News: Lipitor's unlikely success. Johnson. Linda A.. The Journal Gazette. Associated Press. 1 January 2012. 15 June 2014.
5. Winslow, Ron . 2000 . Marketplace: The Birth of a Blockbuster, Lipitor's Route out of the Lab . . online, print . January 24 . 2 February 2016 .
6. Web site: The NAS Award for Chemistry in Service to Society established by E. I. du Pont de Nemours & Company . NAS . 2015 . 16 November 2015.
7. Rowe, Aaron . 2008 . Meet the Guy Who Invented Lipitor . . online . August 20 . 2 February 2016 . Bruce Roth, the inventor of Lipitor, calls the people who make those tough decisions 'drug hunters' and says that it takes between 10 and 15 years to train them. / 'Unfortunately, there are some things that are hard to predict,' said Roth, during a panel discussion this Monday at the American Chemical Society meeting in Philadelphia. 'We still are not very good at understanding which compounds are going to be successful, and which ones will be toxic.' .
8. US . 4681893 . patent . Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis . 21 July 1987 . 20 May 1986 . Roth BD .
9. Roth, B.D. . 2002 . The Discovery and Development of Atorvastatin, a Potent Novel Hypolipidemic Agent . . King, F.D. . Oxford, A.W. . Reitz, Allen B. . Dax, Scott L. . 40 . 1–22 . 978-0-444-51054-9 . 12516521 . 10.1016/S0079-6468(08)70080-8. Progress in Medicinal Chemistry .
10. Simons, John . 2003 . The $10 Billion Pill: Hold the Fries, Please. . online . January 20 . 2 February 2016 . "Subtitle: Lipitor, the cholesterol-lowering drug, has become the bestselling pharmaceutical in history. Here's how Pfizer did it. .
11. Hoefle, Milton L. . 2000 . The Early History of Parke-Davis and Company . . 25 . 1 . 28–34 .
12. Petersen, Melody . 2000 . Pfizer Gets Its Deal to Buy Warner-Lambert for $90.2 Billion . . online, print . February 8 . 2 February 2016 .
13. News: Inventor of Lipitor to speak in Chico. https://archive.today/20140615150309/http://www.redbluffdailynews.com/news/ci_14294056. 2014-06-15. Red Bluff Daily News. 2010-01-29. 15 June 2014.
14. Roth, Bruce D. (2003) "Discovery and development of Lipitor (atorvastatin calcium)," ACS Award for Creative Invention Symposium: New Therapies for Atherosclerosis, MEDI 158 (March 24), The 225th ACS National Meeting, New Orleans, LA, March 23–27, 2003.
15. Web site: Chemical Society to honor "Heroes of Chemistry" during National Meeting. American Chemical Society. 2008-08-13. 15 June 2014.
16. Web site: Bruce Roth, Inventor of Lipitor, to Receive 2013 SCI Perkin Medal in Marketwired . Chemical Heritage Foundation . 3 June 2013 . 24 November 2015 . Philadelphia, PA . https://web.archive.org/web/20160712193620/http://www.chemheritage.org/about/news-and-press/chf-in-the-media/2013-06-03-bruce-roth-to-receive-2013-sci-perkin-medal-in-marketwired.aspx. July 12, 2016.