SCOTT D. LARSEN, Ph.D.
PROFESSIONAL EXPERIENCE
University of Michigan, Ann Arbor, MI
Director of Vahlteich Medicinal Chemistry Core 2012 - present Research Professor of Medicinal Chemistry – College of Pharmacy 2007 - present
Co-Director of Vahlteich Medicinal Chemistry Core 2007 - 2012
Pfizer, Inc., Ann Arbor, MI
Research Fellow – Cardiovascular Chemistry 2003 - 2007
· Group leader (4-8 PhD and BS/MS chemists)
Pharmacia / Pharmacia & Upjohn / The Upjohn Co., Kalamazoo, MI
Associate Director and Fellow – Medicinal Chemistry 2002 - 2003
· Management of 5 PhD and 8 BS/MS chemists
Senior Research Advisor – Medicinal Chemistry 2001 - 2002
Senior Scientist – Combinatorial and Medicinal Chemistry 1997 - 2001
Senior Research Scientist – Medicinal Chemistry 1992 - 1997
Research Scientist – Metabolic Diseases 1988 - 1992
Scientist – Atherosclerosis and Thrombosis 1985 - 1988
EDUCATION
Postdoctoral Research, Indiana University 1984-1985
Advisor: Paul Grieco
Development of novel iminium Diels-Alder cycloadditions
Ph.D. Organic Chemistry, University of Wisconsin-Madison 1983
Thesis Advisor: Edwin Vedejs
Thesis Title: Macrocyclic Pyrrolizidine Alkaloids: The Total
Synthesis of d,l-Fulvine and d,l-Crispatine
B.S. Chemistry (summa cum laude), Alma College, Alma, MI 1979
HONORS AND AWARDS
Alma College Trustees’ Scholarship, 1975-79; Michigan State Competitive Scholarship, 1975-79; Inducted into Phi Sigma Pi Honor Society, 1978 (converted to Alma College Phi Beta Kappa chapter in 1980); ACS Outstanding Undergraduate Chemistry Student Award, Alma College, 1979; B.S. degree awarded summa cum laude 1979; Pharmacia & Upjohn Special Recognition Awards 1998, 2000; Charter Member of the Pharmacia Fellows, 2001; Pfizer Achievement Award, 2007.
TEACHING EXPERIENCE
Graduate Students Mentored
· Chris George (MS, Sep 2009, “CNS-Permeable Inhibitors of Glucosylceramide Synthase”, Ascend Performance Materials)
· Jessica L. Bell (PhD, Aug 2012, “Novel Modulators of Rho Transcriptional Signaling in Cancer”, Asst Prof at Northern Michigan Univ)
· Bryan Yestrepsky (PhD, Aug 2013, “Development of a Novel Class of Multifunctional Virulence-Attenuating Antibiotics”, PSTP Trainee, Paul Hergenrother postdoc at U of Ill)
· Kyle Bolduc (PhD, Aug 2013, “Synthetic and Biocatalytic Methods for the Chemoenzymatic Production of Cryptophycin Analogs”, Global Scholar at PreScouter, Inc.)
· Janice Sindac (PhD expected Aug 2014)
· Scott Barraza (PhD expected Aug 2014, Rackham Merit Scholar)
· Helen Waldschmidt (PhD expected Aug 2017)
Dissertation Committees (completed)
· Jiangwei Yao, Medicinal Chemistry (2010)
· Asako Kubota, Chemistry (2012)
· Elizabeth Girnys, Medicinal Chemistry (2012)
· Lauren Dixon Mishra, Medicinal Chemistry (2013)
· Solymar Negretti, Medicinal Chemistry (2013)
· Xu Ran, Medicinal Chemistry
· Todd Eckroat, Medicinal Chemistry (2013)
· Vanessa Porter, Medicinal Chemistry
· Aubrie Harland, Medicinal Chemistry
· Zapporah Young, Medicinal Chemistry
· Aaron Bender, Medicinal Chemistry
· Carrie Johnson, ChemBio
· Andrew Haak, Pharmacology
Classes
· MedChem 635 “Principles of Drug Design” (University of Michigan, 2008, 2011)
o Creator and director of course
o 7 lectures (drug metabolism, lead selection, chirality, conformational restriction, drug development case histories)
· MedChem 532 “Bioorganic Principles of Medicinal Chemistry” (University of Michigan, 2007-present)
o Coordinator of course 2012-present
o 6 lectures (introduction and drug metabolism)
· ChE/Pharm 519 “Modern Pharmaceutical Engineering” (University of Michigan, 2009-present)
o 1 lecture (medicinal chemistry in drug development)
· PharmD Investigations Review Committee (2009-2012)
· Currently designing new MedChem 533 course “Strategies in Drug Development”
KEY SCIENTIFIC ACCOMPLISHMENTS
Pharmacia/Pfizer
· Design and development of hepatoselective inhibitors of hydroxymethylglutaryl-Coenzyme A (HMG-CoA) reductase. Identification of three clinical candidates.
· Synthesis and development of novel aminoguanidine antidiabetic/antiobesity agents. Identification of one clinical candidate.
· Development of a novel class of inhibitors of AcylCoA:Cholesterol O-Acyltransferase (ACAT) with in vivo cholesterol-lowering activity.
· Design and synthesis of novel seco-oxysterol inhibitors of HMG-CoA reductase gene transcription.
· Design of peptidomimetic PTP1B inhibitors with submicromolar potency through multiple parallel synthesis, enzyme-ligand co-crystallization, and structure-based design.
· Design and synthesis of potent, orally bioavailable non-nucleoside DNA polymerase inhibitors
University of Michigan Vahlteich Medicinal Chemistry Core (VMCC)
· Design of the first glucosylceramide synthase inhibitor that successfully lowers brain glycosphingolipid levels in a mouse model of Sandhoff disease
· From a high throughput screening lead, developed inhibitors of neurotropic arboviral RNA replication with protective effects in mouse models of infection. This is the first example of a small molecule therapeutic that lengthens lifespan in a WEEV infection model.
· Development of inhibitors of Rho-mediated gene transcription that inhibit cancer cell migration and attenuate up-regulation of pro-fibrotic genes in cells from human scleroderma patients
o CCG-203971 significantly attenuates development of fibrosis in a murine model
o Design of a tag-free photoprobe for target identification that retained biological activity and was able to specifically label a protein in whole cells
· Since 2008 the VMCC has collectively contributed to successful grant awards totaling $24.9M to the University of Michigan (including $4.0M to the VMCC) in direct costs.
SUCCESSFUL EXTERNAL GRANT FUNDING
R43 DK083074-01A1 (Hilfinger, PI) 4/1/09-3/31/10
“Development of orally delivered, non-absorbable AT1 receptor antagonists for inflammatory bowel disease treatment”
R21 NS065492 01A1 (Larsen, PI) 9/30/09-11/30/11
“Design of CNS-Permeable Agents for the Treatment of Lipid Storage Diseases”
R01 GM078200-S1 (Rosania, PI) 7/1/10-8/31/12
“Chemical Address Tags: A Cheminformatic & Image Data Management and Analysis Plan - admin supplement”
R21 NS079633-01 (Shayman, PI) 8/1/12-7/31/14
“In vivo proof of efficacy studies for a novel glucosylceramide synthase inhibitor with central nervous system activity”
R21 AI096985-01-A1 (Al-Hashimi, PI) 8/1/12-7/31/14
“Biological Activity of Lead Compounds Targeting HIV-1 TAR RNA”.
P01 HL057346 11A1 (Ginsburg, PI) 4/1/09-3/31/14
“Molecular Genetics of Coagulation Disorders”
R01 HL0270973 (Martens, PI) 4/1/10-3/31/14
“Trafficking and Regulation of Cardiovascular K+ Channels”
2 R01 GM078200-08 (Rosania, PI) 9/1/12-7/31/16
“Chemical Address Tags: A Cheminformatic & Image Data Management and Analysis Plan - admin supplement”
R01 AI089417 (Miller, PI) 7/1/10-6/30/15
“Novel Therapeutics for Neurotropic Alphaviruses”
P30 CA046592 (Wicha, PI) 9/1/12-8/31/17
“University of Michigan Cancer Center Support Grant”
P50 GM103297 (Telenitsky, PI) 9/17/12-8/31/17
“The Center for HIV RNA Studies (CRNA)”
R43 AR065314 (Pape, PI) 8/1/13-7/31/14
“Targeted Small Molecule Medicinal Chemistry for Myotonic Dystrophy”
R43 HL120441 (Baragi, PI) 8/15/13-8/28/14
“Selective MRTF/SRF-Transcription Inhibitors: Novel Anti-Fibrotics”
R01 HD076004 (Larsen, Shayman MPI) 4/1/13-3/31/16
“Novel Probes for Studying Treatment of CNS-based Lysosomal Storage Diseases”
R01 CA174667 (Paczesny, PI) 4/1/13-3/31/16
“High throughput screening (HTS) to discover graft-versus-host disease inhibitors”
R01 AR066049-01 (Larsen, PI) 4/1/14-3/31/17
“Inhibition of the Rho/MRTF/SRF pathway as a new treatment for systemic sclerosis”
PHARMA PROJECT LEADERSHIP EXPERIENCE
Cholesterol Absorption Inhibitors (2006-2007, Pfizer):
· Transitioned exploratory project to full Lead Development stage (9 chemists).
· Contributed to the design of biomarker and early clinical development plans.
· Managed external contract chemistry support
HMG-CoA Reductase Inhibitors (2003-2006, Pfizer):
· Led chemistry team of 10-23 chemists in design and synthesis of over 1800 compounds.
· Advanced three compounds through FIH.
· Assisted in preparation of INDs and design of early clinical development plans.
Protein Tyrosine Phosphatase 1B (1997-1998, Pharmacia):
· Leader of international multidisciplinary team (15-20 scientists) working on the design and development of peptidomimetic inhibitors.
· Successfully identified compounds with cellular activity.
Antihyperglycemic Compounds (1994-1998, Pharmacia):
· Chemistry team leader for two different projects developing novel antihyperglycemics.
· Advanced one compound into FIH (PNU-106817).
CONSULTING
· Metabolic Solutions Development Company, Kalamazoo, MI (2008-present)
PROFESSIONAL MEMBERSHIPS
· American Chemical Society: Divisions of Organic and Medicinal Chemistry (1985 – present)
PROFESSIONAL SERVICE
· ACS Medicinal Chemistry Division Long Range Planning Committee (2005 – 2007)
· NIH Special Emphasis Panel for NIH/NIDA RFA “Pharmacological Development of Treatment Agents and Formulations for Tobacco Dependence” (STTR R41), March 18, 2011.
· NIH NCATS TRND Contract Reviewer (ZTR1 DPI-3), February 28-March 1, 2013
PUBLICATIONS
Internal:
Eighty-eight full Technical Reports at Upjohn/Pharmacia (1985-2003)
External:
1. Vedejs, E., Larsen, S.D. "Total Synthesis of d,l‑Fulvine and d,l‑Crispatine," J. Am. Chem. Soc. 1984, 106, 3030-2.
2. Vedejs, E., Larsen, S., West, F.G "Nonstabilized Imidate Ylides by the Desilylation Method: A Route to the Pyrrolizidine Alkaloids Retronecine and Indicine," J. Org. Chem. 1985, 50, 2170-4.
3. Vedejs, E., Larsen, S. "Hydroxylation of Enolates with oxodiperoxymolybdenum‑(pyridine)(hexamethylphosphoric triamide): 1,7,7‑Trimethyl‑3‑hydroxybicyclo[2.2.1]‑heptan‑2‑one," Org. Synth. 1985, 64, 127.
4. Larsen, S.D., Grieco, P.A. "Aza Diels‑Alder Reactions in Aqueous Solution: Cyclocondensation of Dienes with Simple Iminium Salts Generated under Mannich Conditions," J. Am. Chem. Soc. 1985, 107, 1768-9.
5. Grieco, P.A., Larsen, S.D., Fobare, W.F. "Aza Diels‑Alder Reactions in Water: Cyclocondensation of C‑Acyl Iminium Ions with Cyclopentadiene," Tetrahedron Lett. 1986, 27, 1975-8.
6. Larsen, S.D., Grieco, P.A., Fobare, W.F. "Reactions of Allylsilanes with Simple Iminium Salts in Water: A Facile Route to Piperidines via an Aminomethano Desilylation‑Cyclization Process," J. Am. Chem. Soc. 1986, 108, 3512-13.
7. Grieco, P.A., Larsen, S.D. "An Intramolecular Immonium Ion Variation of the Diels‑Alder Reaction: Synthesis of (±)‑Dihydrocannivonine," J. Org. Chem. 1986, 51, 3553-5.
8. Vedejs, E., Ahmad, S., Larsen, S.D., Westwood, S. "Synthesis of Monocrotaline by Nucleophilic Macrolactonization," J. Org. Chem. 1987, 52, 3937-8.
9. Larsen, S. D. "A Stereoselective Synthesis of Functionalized Cyclopentenes via Base‑Induced Ring Contraction of Thiocarbonyl Diels‑Alder Adducts," J. Am. Chem. Soc. 1988, 110, 5932-4.
10. Larsen, S. D., Martinborough, E. "Cycloaddition of ß‑Substituted Enones to a Bicyclic Sydnone: Observation of an Unexpectedly Facile Hydrocarbon Elimination," Tetrahedron Lett. 1989, 30, 4625-8.
11. Grieco, P. A., Larsen, S. D. "Immonium Ion Based Diels‑Alder Reactions: N‑ Benzyl‑2‑azanorbornene," Org. Synth. 1990, 68, 206-9.
12. Larsen, S. D., Spilman, C. H., Bell, F. P., Dinh, D. M., Martinborough, E., Wilson, G. J. Synthesis and Hypocholesterolemic Activity of 6,7-Dihydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-diones, Novel Inhibitors of AcylCoA:Cholesterol O-Acyltransferase," J. Med. Chem. 1991, 34, 1721-7.
13. Larsen, S.D., Spilman, C.H. "New Potential Therapies for the Treatment of Atherosclerosis," Ann. Rpts. Med. Chem. 1993, 28, 217-26.
14. Larsen, S.D.; Spilman, C.H.; Yagi, Y.; Dinh, D.M.; Hart, K.L.; Hess, G.F. "Design and Synthesis of Seco-Oxysterols Analogs as Potential Inhibitors of 3-Hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) Reductase Gene Transcription", J. Med. Chem 1994, 37, 2343-51.
15. Larsen, S.D. "Regulators of 3-Hydroxy-3-methylglutaryl Coenzyme A Synthesis and Degradation", Drugs of the Future 1995, 20 , 919-27.
16. Larsen, S.D.; Fisher, P.V.; Libby, B.E.; Jensen, R.M.; Mizsak, S.A., Watt, W.; Ronk, W.R.; Hill, S.T. "Cyclopentene Synthesis from 1,3-Dienes via Base-Induced Ring Contraction of 3,6-Dihydro-2H-thiopyrans: Studies on Diastereoselection and Mechanism", J. Org. Chem. 1996, 61, 4725-38.
17. Yagi, Y.; Bevis, D.J.; Hart, K.L.; Hess, G.F.; Dinh, D.M.; Keiser, B.J.; Larsen, S.D.; Spilman, C.H. "Screening for Inhibitors of HMG-CoA Reductase Promoter in HepG2: Identification of Four Non-Oxysterol Inhibitors", Drug Dev. Res. 1997, 40, 41-47.
18. May, P.D.; Larsen, S.D. "Preparation of Novel 6-substituted-4-hydroxy-2-pyrone-3-carboxamides and esters via Palladium Catalyzed Cross Coupling Methodology", Synlett 1997, 895-6.
19. Larsen, S.D. "Novel Parham-type Cycloacylations of 1H-Pyrazole-1-alkanoic Acids", Synlett 1997, 1013-14.
20. Larsen, S.D.; Connell, M.A.; Cudahy, M.M.; Evans, B.R.; May, P.D.; Meglasson, M.D.; O'Sullivan, T.J.; Schostarez, H.J.; Sih, J.C.; Stevens, F.C.; Tanis, S.P.; Tegley, C.M.; Tucker, J.A.; Vaillancourt, V.A.; Vidmar, T.J.; Watt, W.; Yu, J.H. “Synthesis and Biological Activity of Analogues of the Antidiabetic/Antiobesity Agent 3-Guanidinopropionic Acid: Discovery of a Novel Aminoguanidinoacetic Acid Antidiabetic Agent”, J. Med. Chem. 2001, 44, 1217-30.
21. Vaillancourt, V.A.; Larsen, S.D.; Tanis, S.P.; Burr, J.E.; Connell, M.A.; Cudahy, M.M.; Evans, B.R.; Fisher, P.V.; May, P.D.; Meglasson, M.D.; Robinson, D.R.; Stevens, F.C.; Vidmar, T.J.; Yu, J.H.; Tucker, J.A. “Synthesis and Biological Activity of Aminoguanidine and Diaminoguanidine Analogs of the Antidiabetic/Antiobesity Agent 3-Guanidinopropionic Acid”, J. Med. Chem. 2001, 44, 1231-48.
22. Bleasdale, J.E.; Ogg, D.; Palazuk, B.J.; Jacob, C.S.; Swanson, M.L.; Wang, W.-Y.; Thompson, D.P.; Conradi, R.A.; Mathews, W.R.; Laborde, A.L.; Stuchley, C.J.; Heijbel, A.; Bergdahl, K.; Bannow, C.A.; Smith, C.W.; Liljebris, C.; Schostarez, H.J.; May, P.D.; Stevens, F.C.; Larsen, S.D. "Small Molecule Peptidomimetics Containing a Novel Phosphotyrosine Bioisostere Inhibit Protein Tyrosine Phosphatase 1B (PTP1B) and Augment Insulin Action", Biochemistry 2001, 40, 5642-54.
23. Larsen, S.D.; DiPaolo, B.A. “Traceless Solid-Phase Synthesis of 1,2,4-Triazoles Using a Novel Amine Resin”, Org. Lett. 2001, 3, 3341-44.
24. Larsen, S.D.; Barf, T.J.; Liljebris, C.; May, P.D.; Ogg, D.; O'Sullivan, T.J.; Palazuk, B.J.; Schostarez, H.J.; Stevens, F.C.; Bleasdale, J.E. "Synthesis and Biological Activity of a Novel Class of Small Molecular Weight Peptidomimetic Competitive Inhibitors of Protein Tyrosine Phosphatase 1B (PTP1B)", J. Med. Chem. 2002, 45, 598-622.
25. Liljebris, C.; Larsen, S.D.; Ogg, D.; Palazuk, B.J.; Bleasdale, J.E. “Investigation of Potential Bioisosteric Replacements for the Carboxyl Groups of Peptidomimetic Inhibitors of Protein Tyrosine Phosphatase 1B: Identification of a Tetrazole-Containing Inhibitor with Cellular Activity”, J. Med. Chem. 2002, 45, 1785-98.
26. Larsen, S.D.; Stevens, F.C.; Lindberg, T.J.; Bodnar, P.M.; O’Sullivan, T.J.; Schostarez, H.J.; Palazuk, B.J.; Bleasdale, J.E. “Modification of the N-Terminus of Peptidomimetic Protein Tyrosine Phosphatase (PTP1B) Inhibitors: Identification of Analogs with Cellular Activity”, Bioorg. Med. Chem. Lett. 2003, 13, 971-75.
27. Larsen, S.D.; Stachew, C.F.; Clare, P.M.; Cubbage, J.W.; Leach, K.L. “A Catch-and-Release Strategy for the Combinatorial Synthesis of 4-Acylamino-1,3-thiazoles as Potential cdk5 Inhibitors”, Bioorg. Med. Chem. Lett. 2003, 13, 3491-5.
28. Larsen, S.D.; Hester, M.R.; Ruble, J. C.; Kamilar, G.M.; Romero, D.L.; Melchior, E.P.; Sweeney, M.T.; Marotti, K.R. “Discovery and Initial Development of a Novel Class of Antibacterials: Inhibitors of S. aureus Transcription/Translation”, Bioorg. Med. Chem. Lett 2006, 16, 6173-77.
29. Larsen, S.D.; Zhang, Z.; DiPaolo, B.A..; Hageman, T.A.; Hopkins, M.L.; Oien, N.L.; Rohrer, D.C.; Rush, B.D.; Schwende, F.J.; Stefanski, K.J.; Wieber, J.L.; Wilkinson, K.F.; Zamora, K.M. ; Wathen, J.L.; Brideau, R.J “7-Oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamides: Synthesis and Biological Activity of a New Class of Highly Potent Inhibitors of Human Cytomegalovirus DNA Polymerase”, Bioorg. Med. Chem. Lett. 2007, 17, 3840-44.
30. Bratton, L.D.; Auerbach, B.; Choi, C.; Dillon, L.; Hanselman, J.C.; Larsen, S.D.; Lu, G.; Olsen, K.; Pfefferkorn, J.A.; Robertson, A.; Sekerke, C.; Trivedi, B.K.; Unangst, P.C. “Discovery of Pyrrole-based Hepatoselective Ligands as Potent Inhibitors of HMG-CoA Reductase”, Bioorg. Med. Chem. 2007, 15, 5576-89.
31. Pfefferkorn, J.A.; Bowles, D; Kissel, W.; Boyles, D.; Choi, C.; Larsen, S.D.; Song, Y.; Sun, K.-L.; Miller, S.; Trivedi, B.K. “Development of a Practical Synthesis of Novel Pyrrole-Based HMG-CoA Reductase Inhibitors”, Tetrahedron 2007, 63, 8124-34.
32. Pfefferkorn, J.A.; Choi, C.; Song, Y.; Trivedi, B.K. ; Larsen, S.D. ; Askew, V.; Dillon, L.; Hanselman, J.C.; Lin, Z.; Lu, G.; Robertson, A.; Sekerke, C.; Auerbach, B.; Pavlovsky, A.; Harris, M.S.; Bainbridge, G.; Caspers, N. “Design and Synthesis of Novel, Conformationally Restricted HMG-CoA Reductase Inhibitors”, Bioorg. Med. Chem. Lett. 2007, 17, 4531-37.