Anthony Pinkerton's Research Focus
Dr. Pinkerton is an experienced medicinal chemist, who leads MedChem efforts for the Prebys Center at SBP. He and his team drive screening hits to chemical probes or through lead optimization. Below are just a couple of examples of programs on which Tony and his team are currently working, or to which they have contributed. With a team of collaborators from Duke University Tony is leading the chemistry effort for the development of a novel series of NTR1 allosteric modulators, the first example of brain penetrant small molecule NTR1 activators that have been described. These first-in-class compounds are being optimized in to possible drug leads for the treatment of schizophrenia, drug abuse, and other neuropsychiatric disorders. In collaboration with Jose Luis Millan, a professor at SBP as well, Tony is leading the development of the first selective, potent and orally bioavailable tissue non specific alkaline phosphatase (TNAP) inhibitors that have shown strong efficacy in a range of animal models of pathological calcification. These inhibitors could have use in a range of disorders including vascular calcification, generalized arterial calcification of infancy (GACI), calciphylaxis and pseudoxanthoma elasticum (PXE). With a group of scientists from both UCSD and the University of Giessen in Germany, the SBP medicinal chemistry team has developed a series of remarkable potent and selective plasmodium falciparum G6PDH inhibitors as a potential treatment for resistant malaria. The lead compounds are currently in animal testing.
Anthony Pinkerton's Research Report
“Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor” Pinkerton, A.B.; Sergienko, E.; Bravo, Y.; Dahl, R.; Ma, C.-T.; Sun, Q.; Jackson, M. R.; Cosford, N. D. P.; Millan, J.-L. Bioorg. Med. Chem. Letters 2018, 28, 31-34. doi.org/10.1016/j.bmcl.2017.11.024
“Overexpression of Tissue-nonspecific Alkaline Phosphatase (TNAP) in Endothelial Cells Accelerates Coronary Artery Disease in a Mouse Model of Familial Hypercholesterolemia”Romanelli, F.; Corbo, A.; Salehi, M.; Yadav, M. C.; Salman, S.; Petrosian, D.; Rashidbaigi, O.J.; Chait, J.; Kuruvilla, J.; Plummer, M.; Radichev, I.; Margulies, K. B.; Gerdes, A. M.; Pinkerton, A. B.; Millan, J.L.; Savinov, A. Y.; Savinova, O. V. PLOS One 2017, 12(10): e0186426. doi.org/10.1371/journal.pone.0186426
“Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue non-specific alkaline phosphatase” Ziegler, S.; Chew, E.; Dietz, H.; Millan, J.-L.; Pinkerton, A. B.; Gahl, W.; Ferreira, C.; MacFarlane, E.; Riddle, R.; Tomlinson, R.; Martin, L.; Ma, C.-T.; Sergienko, E. Science Translational Medicine 2017, 9(393). doi: 10.1126/scitranslmed.aal1669
Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification” Sheen, C. R.; Kuss, P.; Narisawa, S.; Yadav, M. C.; Nigro, J.; Wang, W.; Chhea, T. N.; Sergienko, E. A.; Kapoor, K.; Jackson, M. R.; Hoylaerts, M. F.; Pinkerton, A. B.; O’Neill, W. C.; Millan, J. L. Journal of Bone and Mineral Research2015, 30 (5), 824-836
Inhibitors of Tissue-Nonspecific Alkaline Phosphatase (TNAP): From Hits to Leads” Teriete, P.; Pinkerton, A. B.; Cosford, N. D. P., Methods in Molecular Biology,2013, 1053, 85-101
PCT WO 2016054056 “Methods of treating disorders characterized by medial vascular calcification with an inhibitor of tissue-nonspecific alkaline phosphatase” Gahl, W. A.; Ziegler, S. G.; Dietz, H. C.; Pinkerton, A. B.; Millan, J. L
PCT WO 2013126608 “Preparation of pyridinylsulfonamidedervatives for use as TNAP inhibitor” Pinkerton, A. B.; Dahl, R.; Cosford, N. D. P.; Millan, J. L.
“ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse” Barak, L.S.; Bai, Y.; Peterson, S.; Evron, T.; Urs, N. M.; Peddibhotla, S.; Hedrick, M. P.; Hershberger, P.; Maloney, P. R.; Chung, T. D. Y.; Rodriguiz, R. M.; Wetsel, W. C.; Thomas, J. B.; Hanson, G. R.; Pinkerton, A. B.; Caron, M. G. ACS Chemical Biology 2016 11(7), 1880-1890. DOI:10.1021/acschembio.6b00291
Peddibhotla, S.; Hedrick, M. P.; Hershberger, P.; Maloney, P. R.; Li, Y.; Milewski, M.; Gosalia, P.; Gray, W.; Mehta, A.; Sugarman, E.; Hood, B; Suyama, E.; Nguyen, K.; Heynen-Genel, S.; Vasile, S.; Salaniwal, S.; Stonich, D.; Su, Y.; Mangravita-Novo, A.; Vicchiarelli, M.; Roth, G. P.; Smith L. H.; Chung, T. D. Y; Hanson, G. R.; Thomas, J. B.; Caron, M. G.; Barak, L. S.; Pinkerton, A. B. (2013) “Discovery of ML314, a Brain Penetrant Non-Peptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor” ACS Medicinal Chemistry Letters, 4, 846-851. PMCID: PMC3940307.
Hershberger, P. M.; Hedrick, M. P.; Peddibhotla, S.; Mangravita-Novo, A.; Gosalia, P.; Li, Y.; Gray, W.; Vicchiarelli, M.; Smith, L. H.; Chung, T. D. Y.; Thomas, J. B.; Caron, M. G.; Pinkerton, A. B.; Barak, L. S.; Roth G. P. (2013) “Imidazole-derived agonists for the neurotensin 1 receptor” Bioorg. Med. Chem. Letters, Bioorg Med Chem Lett. 2014 Jan 1;24(1):262-7. doi: 10.1016/j.bmcl.2013.11.026. PMID: 24332089. PMCID: PMC3898338.
PCT WO 2015200534 “Preparation of substituted quinazolines as small molecule agonists of neurotensin receptor 1” Pinkerton, A. B.; Hershberger, P. M.; Peddibhotla, S.; Maloney, P. R.; Hedrick, M. P
PCT WO 2014100501 “Preparation of piperazinylquinazolines and related compounds as agonists of neurotensin receptor 1” Pinkerton, A.; Maloney, P.; Hershberger, S.; Peddibhotla, S.; Hedrick, M.; Barak, L.; Caron, M.
“Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase” Stanford, S. M.; Aleshin, A. E.; Zhang, V.; Ardecky, R. J.; Hedrick, M.P.; Zou, J.; Ganji, S. R.; Bliss, M. R.; Yamamoto, F.; Bobkov, A. A.; Kiselar, J.; Liu, Y.; Cadwell, G. W.; Khare, S.; Yu, J.; Barquilla, A.; Chung, T. D. Y.; Mustelin, T.; Schenk, S.; Bankston, L. A.; Liddington, R. C.; Pinkerton, A. B.; Bottini, N., Nature Chemical Biology 2017, 13, 624-632. doi:10.1038/nchembio.2344
PCT WO 2016061280 “Inhibitors of low molecular weight protein tyrosine phosphatase and uses thereof” Bottini, N.; Zou, J.; Ganji, S.R.; Stanford, S.; Pinkerton, A.; Chung, T.; Hedrick, M.; Ardecky, R
Anthony Pinkerton's Bio
Dr. Pinkerton’s career in industry began as a medicinal chemist at the Merck Research Laboratories in San Diego. Over his career, Tony has worked in multiple therapeutic areas including CNS, virology, diabetes, inflammation, and oncology, with extensive experience in GPCRs. He has been both project leader and project manager for oncology, virology and diabetes targets, as well as chemistry lead for the metabolic disease therapeutic area group, in which he helped a team identify and prosecute the most promising new targets in the field. In addition, Tony has led the IP strategy around multiple chemical series and programs. Tony is an inventor or co-inventor on over 40 patents or patent applications covering small molecule therapeutics, as well as over 70 publications. During his career he has helped advance multiple compounds into clinical development.
Tony originally trained as a synthetic organic chemist in the laboratories of Dieter Seebach at ETH-Zurich (where he was a Fulbright Scholar) and Barry Trost at Stanford University, where he earned his Ph.D. in chemistry in 2001. While at Stanford he developed new metal catalyzed reactions and completed the total synthesis of several natural products.