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Publication
Featured researches published by Zhili Sun.
Journal of Medicinal Chemistry | 2011
Qun Dang; Yan Liu; Daniel K. Cashion; Srinivas Rao Kasibhatla; Tao Jiang; Frank Taplin; Jason D. Jacintho; Haiqing Li; Zhili Sun; Yi Fan; Jay DaRe; Feng Tian; Wenyu Li; Tony Gibson; Robert H. Lemus; Paul D. van Poelje; Scott C. Potter; Mark D. Erion
Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.
ACS Medicinal Chemistry Letters | 2010
Jorge E. Gomez-Galeno; Qun Dang; Thanh Huu Nguyen; Serge H. Boyer; Matthew P. Grote; Zhili Sun; Mingwei Chen; William Craigo; Paul D. van Poelje; Deidre A. MacKenna; Edward E. Cable; Paul A. Rolzin; Patricia D. Finn; Bert Chi; David L. Linemeyer; Scott J. Hecker; Mark D. Erion
AMP-activated protein kinase (AMPK) is a heterotrimeric kinase that regulates cellular energy metabolism by affecting energy-consuming pathways such as de novo lipid biosynthesis and glucose production as well as energy-producing pathways such as lipid oxidation and glucose uptake. Accordingly, compounds that activate AMPK represent potential drug candidates for the treatment of hyperlipidemia and type 2 diabetes. Screening of a proprietary library of AMP mimetics identified the phosphonic acid 2 that bears little structural resemblance to AMP but is capable of activating AMPK with high potency (EC50 = 6 nM vs AMP EC50 = 6 μM) and specificity. Phosphonate prodrugs of 2 inhibited de novo lipogenesis in cellular and animal models of hyperlipidemia.
Journal of Medicinal Chemistry | 2008
K. Raja Reddy; Michael C. Matelich; Bheemarao G. Ugarkar; Jorge E. Gomez-Galeno; Jay DaRe; Kristin Ollis; Zhili Sun; William Craigo; Timothy J. Colby; James M. Fujitaki; Serge H. Boyer; Paul D. van Poelje; Mark D. Erion
Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were synthesized with the rationale that this selectively liver-activated prodrug class would enhance liver levels of the active metabolite adefovir diphosphate (ADV-DP) and/or decrease kidney exposure. The lead prodrug (14, MB06866, pradefovir), identified from a variety of in vitro and in vivo assays, exhibited good oral bioavailability (F = 42%, mesylate salt, rat) and rate of prodrug conversion to ADV-DP. Tissue distribution studies in the rat using radiolabeled materials showed that cyclic 1-aryl-1,3-propanyl prodrugs enhance the delivery of adefovir and its metabolites to the liver, with pradefovir exhibiting a 12-fold improvement in the liver/kidney ratio over adefovir dipivoxil.
Antimicrobial Agents and Chemotherapy | 2011
Steven S. Carroll; Kenneth A. Koeplinger; Marissa Vavrek; Nanyan Rena Zhang; Laurence Handt; Malcolm MacCoss; David B. Olsen; K. Raja Reddy; Zhili Sun; Paul D. van Poelje; James M. Fujitaki; Serge H. Boyer; David L. Linemeyer; Scott J. Hecker; Mark D. Erion
ABSTRACT Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide, and the current standard of care, a combination of pegylated interferon alpha and ribavirin, is efficacious in achieving sustained viral response in ∼50% of treated patients. Novel therapies under investigation include the use of nucleoside analog inhibitors of the viral RNA-dependent RNA polymerase. NM283, a 3′-valyl ester prodrug of 2′-C-methylcytidine, has demonstrated antiviral efficacy in HCV-infected patients (N. Afdhal et al., J. Hepatol. 46[Suppl. 1]:S5, 2007; N. Afdhal et al., J. Hepatol. 44[Suppl. 2]:S19, 2006). One approach to increase the antiviral efficacy of 2′-C-methylcytidine is to increase the concentration of the active inhibitory species, the 5′-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2′-C-methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacy in vivo, the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by ∼1.4 log10 IU/ml and by >3.6 log10 IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.
Journal of Medicinal Chemistry | 2007
Scott J. Hecker; K. Raja Reddy; Paul D. van Poelje; Zhili Sun; Wenjian Huang; Vaibhav Varkhedkar; M. Venkat Reddy; James M. Fujitaki; David B. Olsen; Kenneth A. Koeplinger; Serge H. Boyer; David L. Linemeyer; Malcolm Maccoss; Mark D. Erion
Journal of Medicinal Chemistry | 2006
Serge H. Boyer; Zhili Sun; Hongjian Jiang; Julie Esterbrook; Jorge E. Gomez-Galeno; William Craigo; K. Raja Reddy; Bheemarao G. Ugarkar; Deidre A. MacKenna; Mark D. Erion
Archive | 2008
Jorge E. Gomez-Galeno; Raja K. Reddy; Poelje Paul D. Van; Robert H. Lemus; Thanh Huu Nguyen; Matthew P. Grote; Qun Dang; Scott J. Hecker; Venkat Reddy Mali; Mingwei Chen; Zhili Sun; Serge H. Boyer; Haiqing Li; William Craigo
Archive | 2003
K. Raja Reddy; William Craigo; Zhili Sun; Serge H. Boyer; Bheemarao G. Ugarkar
Archive | 2008
Brett C. Bookser; Scott J. Hecker; K. Raja Reddy; David Bernard Smith; Zhili Sun
Archive | 2005
William Craigo; Zhili Sun