SCOTT D. LARSEN, Ph.D.
PROFESSIONAL EXPERIENCE
University of Michigan, Ann Arbor, MI
Joseph Burckhalter Collegiate Research Professor 2014 - present
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
Phi Sigma Pi Honor Society, 1979 (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
UM Collegiate Research Professor Award, 2014
TEACHING EXPERIENCE
Graduate Students Mentored (degree, date, initial postgraduate position(s) attained)
· Chris George (MS, Sep 2009, “CNS-Permeable Inhibitors of Glucosylceramide Synthase”, chemist at Ascend Performance Materials)
· Jessica Bell (PhD, Aug 2012, “Novel Modulators of Rho Transcriptional Signaling in Cancer”, Assistant Professor of Chemistry at Northern Michigan Univ)
· Bryan Yestrepsky (PhD, Aug 2013, “Development of a Novel Class of Multifunctional Virulence-Attenuating Antibiotics”, PSTP Trainee, ACS postdoctoral fellow with Paul Hergenrother at U of Illinois, scientist at AbbVie, Worchester, MA)
· Kyle Bolduc (PhD, Aug 2013, “Synthetic and Biocatalytic Methods for the Chemoenzymatic Production of Cryptophycin Analogs”, postdoc at Wolfe Labs, scientist at BASF)
· Janice Sindac (PhD, Aug 2014, “Development of Small Molecule Replication Inhibitors Against Western Equine Encephalitis Virus”, scientist at Tetra Discovery Partners, Kalamazoo, MI)
· Scott Barraza (PhD, Aug 2014, “Development of Novel Small Molecule Inhibitors of Neurotropic Alphavirus Replication”, postdoc with Scott Denmark at U of Illinois)
· Helen Waldschmidt (PhD expected Aug 2017, AHA Predoctoral Fellow 2015-2017)
· Jeff Zwicker (PhD expected Aug 2018, PSTP Trainee)
· Brandt Huddle (PhD expected Aug 2018)
· Dylan Kahl (PhD expected Aug 2019)
Dissertation Committees (year 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)
· Todd Eckroat, Medicinal Chemistry (2013)
· Xu Ran, Medicinal Chemistry (2014)
· Andrew Haak, Pharmacology (2014)
· Aubrie Harland, Medicinal Chemistry (2016)
· Aaron Bender, Medicinal Chemistry (2016)
· Zapporah Young, Medicinal Chemistry (2016)
· Carrie Johnson, ChemBio
· Tyler Beyett, ChemBio
· Megan Stewart, Medicinal Chemistry
· Allie Sowa, Medicinal Chemistry
· Erin Gallagher, Medicinal Chemistry
· Anthony Nastase, Medicinal Chemistry
· Sean Henry, Medicinal Chemistry
Classes
· MedChem 532 “Bioorganic Principles of Medicinal Chemistry” (University of Michigan, 2007-2015, annual)
o Coordinator of course 2012-2015
o 6 lectures (introduction and drug metabolism)
· MedChem 533 “Strategies in Drug Development” (University of Michigan, 2015)
o Creator and coordinator of course
o 6 lectures (lead selection, chirality, conformational restriction, drug metabolism, drug development case history)
o Proctored and graded eight drug development case history team presentations
· MedChem 535 “Principles of Drug Design” (University of Michigan, planned to start Winter 2017, biannual)
o Creator and coordinator of course
o New addition to core med chem curriculum
· MedChem 635 “Principles of Drug Design” (University of Michigan, 2008, 2011)
o Creator and coordinator of course
o 7 lectures (drug metabolism, lead selection, chirality, conformational restriction, drug development case histories)
· ChE/Pharm 519 “Modern Pharmaceutical Engineering” (University of Michigan, 2009-2015)
o 1 lecture (medicinal chemistry in drug development)
· PharmD Investigations Review Committee (2009-2012)
SUCCESSFUL EXTRAMURAL GRANT FUNDING
R21/R33 AI127492-01 (Larsen, Carruthers MPI) 9/1/16-8/31/21
“Rational design of CNS-permeable cathepsin L inhibitors for treatment of chronic toxoplasmosis”
R01 GM115459-01A1 (Neubig, PI) 4/1/16-3/31/19
“Mechanisms of inhibitors of MRTF/SRF-regulated gene transcription”
R01 AI116605-01A1 (Abramovitch, PI) 12/1/15-11/30/20
“Mechanisms of Mycobacterium Tuberculosis pH-driven Adaptation”
R01 HL071818-11A1 (Tesmer, PI) 7/1/15-6/30/19
“Structure, function, and inhibition of G protein-coupled receptor kinases”
UH2/UH3 NS092981-01 (Larsen, Shayman MPI) 7/1/15-6/30/20
“The Development of Small Molecule Inhibitors for Gaucher Disease Type 3”
R21 AI111182-01 (Trievel, PI) 9/1/14-8/31/16
“Homocitrate Synthase Inhibitors as Novel Antifungal Agents for Aspergillus”
R01 AR066049-01 (Larsen, PI) 5/1/14-4/30/17
“Inhibition of the Rho/MRTF/SRF pathway as a new treatment for systemic sclerosis”
R43 HL120441 (Baragi, PI) 8/15/13-8/28/14
“Selective MRTF/SRF-Transcription Inhibitors: Novel Anti-Fibrotics”
R43 AR065314 (Pape, PI) 8/1/13-7/31/14
“Targeted Small Molecule Medicinal Chemistry for Myotonic Dystrophy”
R01 CA174667 (Paczesny, PI) 4/1/13-3/31/16
“High throughput screening (HTS) to discover graft-versus-host disease inhibitors”
R01 HD076004 (Larsen, Shayman MPI) 4/1/13-3/31/16
“Novel Probes for Studying Treatment of CNS-based Lysosomal Storage Diseases”
P50 GM103297 (Telenitsky, PI) 9/17/12-8/31/17
“The Center for HIV RNA Studies (CRNA)”
P30 CA046592 (Wicha, PI) 9/1/12-8/31/17
“University of Michigan Cancer Center Support Grant”
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”
R21 AI096985-01-A1 (Al-Hashimi, PI) 8/1/12-7/31/14
“Biological Activity of Lead Compounds Targeting HIV-1 TAR RNA”.
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”
R01 AI089417 (Miller, PI) 7/1/10-6/30/15
“Novel Therapeutics for Neurotropic Alphaviruses”
R01 GM078200-S1 (Rosania, PI) 7/1/10-8/31/12
“Chemical Address Tags: A Cheminformatic & Image Data Management and Analysis Plant”
R01 HL0270973 (Martens, PI) 4/1/10-3/31/14
“Trafficking and Regulation of Cardiovascular K+ Channels”
R21 NS065492 01A1 (Larsen, PI) 9/30/09-11/30/11
“Design of CNS-Permeable Agents for the Treatment of Lipid Storage Diseases”
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”
P01 HL057346 11A1 (Ginsburg, PI) 4/1/09-3/31/15
“Molecular Genetics of Coagulation Disorders”
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 $41.4 M to the University of Michigan or other external partners (including $8.1 M to the VMCC) in direct costs.
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
· NIH NINDS NSD-A Study Section, February 22-23, 2016
PUBLICATIONS
Internal:
Eighty-eight full Technical Reports at Upjohn/Pharmacia (1985-2003)
External:
1. Vedejs, E., Larsen, S.D. "Total Synthesis of d,lFulvine and d,lCrispatine," 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): 1,7,7Trimethyl3hydroxybicyclo[2.2.1]heptan2one," Org. Synth. 1985, 64, 127.
4. Larsen, S.D., Grieco, P.A. "Aza DielsAlder 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 DielsAlder Reactions in Water: Cyclocondensation of CAcyl 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 DesilylationCyclization Process," J. Am. Chem. Soc. 1986, 108, 3512-13.
7. Grieco, P.A., Larsen, S.D. "An Intramolecular Immonium Ion Variation of the DielsAlder 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 BaseInduced Ring Contraction of Thiocarbonyl DielsAlder Adducts," J. Am. Chem. Soc. 1988, 110, 5932-4.
10. Larsen, S. D., Martinborough, E. "Cycloaddition of ßSubstituted 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 DielsAlder Reactions: N Benzyl2azanorbornene," 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.