Rosemary Zhang

Publications (11)38.85 Total impact

• Article: Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38α MAP kinase inhibitors.

  Alaric J Dyckman, Tianle Li, Sidney Pitt, Rosemary Zhang, Ding Ren Shen, Kim W McIntyre, Kathleen M Gillooly, David J Shuster, Arthur M Doweyko, John S Sack, Kevin Kish, Susan E Kiefer, John A Newitt, Hongjian Zhang, Punit H Marathe, Murray McKinnon, Joel C Barrish, John H Dodd, Gary L Schieven, Katerina Leftheris
  [show abstract] [hide abstract]
  ABSTRACT: Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
  Bioorganic & medicinal chemistry letters 05/2011; 21(15):4633-7. · 2.65 Impact Factor
• Article: Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors.

  Shuqun Lin, Stephen T Wrobleski, John Hynes, Sidney Pitt, Rosemary Zhang, Yi Fan, Arthur M Doweyko, Kevin F Kish, John S Sack, Mary F Malley, Susan E Kiefer, John A Newitt, Murray McKinnon, James Trzaskos, Joel C Barrish, John H Dodd, Gary L Schieven, Katerina Leftheris
  [show abstract] [hide abstract]
  ABSTRACT: The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.
  Bioorganic & medicinal chemistry letters 10/2010; 20(19):5864-8. · 2.65 Impact Factor
• Article: 5-amino-pyrazoles as potent and selective p38α inhibitors.

  Jagabandhu Das, Robert V Moquin, Alaric J Dyckman, Tianle Li, Sidney Pitt, Rosemary Zhang, Ding Ren Shen, Kim W McIntyre, Kathleen Gillooly, Arthur M Doweyko, John A Newitt, John S Sack, Hongjian Zhang, Susan E Kiefer, Kevin Kish, Murray McKinnon, Joel C Barrish, John H Dodd, Gary L Schieven, Katerina Leftheris
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.
  Bioorganic & medicinal chemistry letters 10/2010; 20(23):6886-9. · 2.65 Impact Factor
• Article: Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38 alpha MAP kinase inhibitors.

  Stephen T Wrobleski, Shuqun Lin, John Hynes, Hong Wu, Sidney Pitt, Ding Ren Shen, Rosemary Zhang, Kathleen M Gillooly, David J Shuster, Kim W McIntyre, Arthur M Doweyko, Kevin F Kish, Jeffrey A Tredup, Gerald J Duke, John S Sack, Murray McKinnon, John Dodd, Joel C Barrish, Gary L Schieven, Katerina Leftheris
  [show abstract] [hide abstract]
  ABSTRACT: A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38 alpha enzyme.
  Bioorganic & medicinal chemistry letters 05/2008; 18(8):2739-44. · 2.65 Impact Factor
• Article: Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors.

  Jagabandhu Das, Robert V Moquin, Sidney Pitt, Rosemary Zhang, Ding Ren Shen, Kim W McIntyre, Kathleen Gillooly, Arthur M Doweyko, John S Sack, Hongjian Zhang, Susan E Kiefer, Kevin Kish, Murray McKinnon, Joel C Barrish, John H Dodd, Gary L Schieven, Katerina Leftheris
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
  Bioorganic & medicinal chemistry letters 05/2008; 18(8):2652-7. · 2.65 Impact Factor
• Article: The discovery of (R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl) thiazole-5-carboxamide (BMS-640994)-A potent and efficacious p38alpha MAP kinase inhibitor.

  John Hynes, Hong Wu, Sidney Pitt, Ding Ren Shen, Rosemary Zhang, Gary L Schieven, Kathleen M Gillooly, David J Shuster, Tracy L Taylor, XiaoXia Yang, [......], Hongjian Zhang, Punit H Marathe, Arthur M Doweyko, Kevin Kish, Susan E Kiefer, John S Sack, John A Newitt, Joel C Barrish, John Dodd, Katerina Leftheris
  [show abstract] [hide abstract]
  ABSTRACT: A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.
  Bioorganic & medicinal chemistry letters 04/2008; 18(6):1762-7. · 2.65 Impact Factor
• Article: Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation.

  Andrew E Schade, Gary L Schieven, Robert Townsend, Anna M Jankowska, Vojkan Susulic, Rosemary Zhang, Hadrian Szpurka, Jaroslaw P Maciejewski
  [show abstract] [hide abstract]
  ABSTRACT: Dasatinib is an oral small molecule inhibitor of Abl and Src family tyrosine kinases (SFK), including p56(Lck) (Lck). Given the central importance of Lck in transmitting signals from the T-cell receptor (TCR) signaling complex and the potent ability of dasatinib to inhibit Lck activity, we hypothesized this agent could provide a novel route of immunomodulation via targeted inhibition of antigen-induced signaling. Herein, we show that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses. However, dasatinib-mediated inhibition does not induce apoptosis because the effect is reversible or may be overcome by signals bypassing the TCR, such as phorbol ester. Signal transduction and proliferative responses via IL-2 remain essentially unperturbed, suggesting that dasatinib displays specificity for TCR signaling. In addition, dasatinib combined with cyclosporine A or rapamycin led to a much more potent inhibition of T-cell activation, suggesting that targeted inhibition of Lck could be a useful adjunct for enhanced immunomodulation. In combination with currently available immunomodulatory agents, SFK inhibition could potentially increase immunomodulatory efficacy while minimizing toxicity of individual agents.
  Blood 03/2008; 111(3):1366-77. · 9.90 Impact Factor
• Article: Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38alpha mitogen-activated protein kinase inhibitors.

  John Hynes, Alaric J Dyckman, Shuqun Lin, Stephen T Wrobleski, Hong Wu, Kathleen M Gillooly, Steven B Kanner, Herinder Lonial, Derek Loo, Kim W McIntyre, [......], Arthur M Doweyko, John S Tokarski, John S Sack, Matthew Pokross, Susan E Kiefer, John A Newitt, Joel C Barrish, John Dodd, Gary L Schieven, Katerina Leftheris
  [show abstract] [hide abstract]
  ABSTRACT: A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFalpha). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.
  Journal of Medicinal Chemistry 02/2008; 51(1):4-16. · 5.25 Impact Factor
• Article: The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase.

  Katerina Leftheris, Gulzar Ahmed, Ran Chan, Alaric J Dyckman, Zahid Hussain, Kan Ho, John Hynes, Jeffrey Letourneau, Wei Li, Shuqun Lin, [......], David Diller, Arthur Doweyko, John Sack, Jack Baldwin, Joel Barrish, John Dodd, Ian Henderson, Steve Kanner, Gary L Schieven, Maria Webb
  [show abstract] [hide abstract]
  ABSTRACT: A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38 alpha protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.
  Journal of Medicinal Chemistry 01/2005; 47(25):6283-91. · 5.25 Impact Factor
• Article: Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors.

  Ping Chen, Derek Norris, Jagabandhu Das, Steven H Spergel, John Wityak, Leslie Leith, Rulin Zhao, Bang-Chi Chen, Sidney Pitt, Suhong Pang, Ding Ren Shen, Rosemary Zhang, Henry F De Fex, Arthur M Doweyko, Kim W McIntyre, David J Shuster, Kamelia Behnia, Gary L Schieven, Joel C Barrish
  [show abstract] [hide abstract]
  ABSTRACT: A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.
  Bioorganic & Medicinal Chemistry Letters 01/2005; 14(24):6061-6. · 2.55 Impact Factor
• Article: Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38α MAP kinase inhibitors

  Stephen T. Wrobleski, Shuqun Lin, John Hynes Jr, Hong Wu, Sidney Pitt, Ding Ren Shen, Rosemary Zhang, Kathleen M. Gillooly, David J. Shuster, Kim W. McIntyre, Arthur M. Doweyko, Kevin F. Kish, Jeffrey A. Tredup, Gerald J. Duke, John S. Sack, Murray McKinnon, John Dodd, Joel C. Barrish, Gary L. Schieven, Katerina Leftheris
  Bioorganic & Medicinal Chemistry Letters. 18(8):2739-2744.