Mark E Fraley

Publications (26)72.52 Total impact

• Article: Pyridyl aminothiazoles as potent inhibitors of Chk1 with slow dissociation rates.

  Vadim Y Dudkin, Keith Rickert, Constantine Kreatsoulas, Cheng Wang, Kenneth L Arrington, Mark E Fraley, George D Hartman, Yowei Yan, Mari Ikuta, Steven M Stirdivant, Robert A Drakas, Eileen S Walsh, Kelly Hamilton, Carolyn A Buser, Robert B Lobell, Laura Sepp-Lorenzino
  [show abstract] [hide abstract]
  ABSTRACT: Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.
  Bioorganic & medicinal chemistry letters 02/2012; 22(7):2609-12. · 2.65 Impact Factor
• Article: Pyridyl aminothiazoles as potent Chk1 inhibitors: optimization of cellular activity.

  Vadim Y Dudkin, Cheng Wang, Kenneth L Arrington, Mark E Fraley, George D Hartman, Steven M Stirdivant, Robert A Drakas, Keith Rickert, Eileen S Walsh, Kelly Hamilton, Carolyn A Buser, James Hardwick, Weikang Tao, Stephen C Beck, Xianzhi Mao, Robert B Lobell, Laura Sepp-Lorenzino
  [show abstract] [hide abstract]
  ABSTRACT: Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.
  Bioorganic & medicinal chemistry letters 02/2012; 22(7):2613-9. · 2.65 Impact Factor
• Article: Discovery of Oxazolobenzimidazoles as Positive Allosteric Modulators for the mGluR2 Receptor

  Robert M. Garbaccio, Edward J. Brnardic, Mark E. Fraley, George D. Hartman, Pete H. Hutson, Julie A. O'Brien, Brian C. Magliaro, Jason M. Uslaner, Sarah L. Huszar, Kerry L. Fillgrove, James H. Small, Cuyue Tang, Yuhsin Kuo, Marlene A. Jacobson
  [show abstract] [hide abstract]
  ABSTRACT: Novel oxazolobenzimidazoles are described as potent and selective positive allosteric modulators of the metabotropic glutamate receptor 2. The discovery of this class and optimization of its physical and pharmacokinetic properties led to the identification of potent and orally bioavailable compounds (20 and 21) as advanced leads. Compound 20 (TBPCOB) was shown to have robust activity in a PCP-induced hyperlocomotion model in rat, an assay responsive to clinical antipsychotic treatments for schizophrenia.Keywords: Oxazolobenzimidazoles; allosteric modulators; metabotropic glutamate 2 receptor; hyperlocomotion model; schizophrenia; GPCR
  07/2010;
• Article: 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts.

  Edward J Brnardic, Mark E Fraley, Robert M Garbaccio, Mark E Layton, John M Sanders, Chris Culberson, Marlene A Jacobson, Brian C Magliaro, Pete H Hutson, Julie A O'Brien, Sarah L Huszar, Jason M Uslaner, Kerry L Fillgrove, Cuyue Tang, Yuhsin Kuo, Sylvie M Sur, George D Hartman
  [show abstract] [hide abstract]
  ABSTRACT: Hit to lead optimization of (5R)-5-hexyl-3-phenyl-1,3-oxazolidin-2-one as a positive allosteric modulator of mGluR2 is described. Improvements in potency and metabolic stability were achieved through SAR on both ends of the oxazolidinone. An optimized lead compound was found to be brain penetrant and active in a rat ketamine-induced hyperlocomotion model for antipsychotic activity.
  Bioorganic & medicinal chemistry letters 05/2010; 20(10):3129-33. · 2.65 Impact Factor
• Article: Stereospecific reduction of a potent kinesin spindle protein (KSP) inhibitor in human tissues.

  Chunze Li, Bing Lu, Robert M Garbaccio, Edward S Tasber, Mark E Fraley, George D Hartman, Jingjing Ye, Jane C Harrelson, Thomayant Prueksaritanont
  [show abstract] [hide abstract]
  ABSTRACT: Compound A, 1-{(3R,3aR)-3-[3-(4-acetylpiperazin-1-yl)propyl]-7-fluoro-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl}ethanone, is a novel and potent inhibitor of the mitotic kinesin spindle protein. Metabolism studies with human hepatocytes showed that Compound A underwent significant ketone reduction to its biologically active metabolite M1. Here, we describe the studies that characterized the metabolic interconversion between Compound A and M1 in vitro in human tissues. LC-MS/MS analysis showed that the ketone reduction was stereospecific for M1 with no diastereomer of M1 detected in incubations with human hepatocytes. Interestingly, such stereospecific ketone reduction was not observed with Compound B, the enantiomer of Compound A. No reductive products were observed when Compound B was incubated with human hepatocytes. Studies with human liver subcellular fractions showed that Compound A was reduced to M1 primarily by human liver cytosol with little contribution from human liver microsomes and mitochondria. NADPH was the preferred cofactor for the reduction reaction. Reverse oxidation of M1 back to Compound A was also observed, preferentially in human liver cytosol with NADP(+) as the cofactor. The interconversion between Compound A and M1 in human liver cytosol was inhibited significantly by flufenamic acid and phenolphthalein (potent inhibitors for aldo-keto reductase 1Cs, p<0.05), but not by menadione, a selective inhibitor for carbonyl reductase. In addition to the liver, S9 from human lung and kidney was also capable of catalyzing this interconversion. Collectively, the results implicated the aldo-keto reductase 1Cs as the most likely enzymes responsible for the metabolic interconversion of Compound A and its active metabolite M1.
  Biochemical pharmacology 05/2010; 79(10):1526-33. · 4.25 Impact Factor
• Article: Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia.

  Mark E Fraley
  [show abstract] [hide abstract]
  ABSTRACT: Normalization of excessive glutamate neurotransmission through activation of the metabotropic glutamate receptor 2 (mGluR2) represents a novel and promising approach for the treatment of schizophrenia. This strategy has gained support through the evaluation of dual mGluR2/3 agonists that act directly at the glutamate (orthosteric) binding site. Importantly, clinical validation of the mechanism was achieved in a Phase II study in schizophrenia patients with mGluR2/3 agonist LY404039. Selective positive allosteric modulators (potentiators) of mGluR2 that bind to the transmembrane region of the receptor have shown efficacy in rodent models predictive of antipsychotic activity, but have yet to be evaluated in the clinic. Allosteric mGluR2 potentiators may offer advantages over orthosteric mGluR2/3 agonists as a result of their unique mode of action and ability to achieve superior mGluR2 selectivity. This review focuses on the structures and biological activities of small molecule potentiators of mGluR2 that appeared in the patent literature between 2006 and early 2009. Potent mGluR2 potentiators that span a broad range of structural diversity have been disclosed. Narrow patent filings within select series and drug-like properties of corresponding preferred compounds suggest that development candidates have likely been nominated.
  Expert Opinion on Therapeutic Patents 07/2009; 19(9):1259-75. · 3.57 Impact Factor
• Article: Development of thioquinazolinones, allosteric Chk1 kinase inhibitors.

  Antonella Converso, Timothy Hartingh, Robert M Garbaccio, Edward Tasber, Keith Rickert, Mark E Fraley, Youwei Yan, Constantine Kreatsoulas, Steve Stirdivant, Bob Drakas, [......], Stephen C Beck, Weikang Tao, Rob Lobell, Laura Sepp-Lorenzino, Joan Zugay-Murphy, Vinod Sardana, Sanjeev K Munshi, Sylvie Marie Jezequel-Sur, Paul D Zuck, George D Hartman
  [show abstract] [hide abstract]
  ABSTRACT: A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at K(m) for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability. An X-ray crystal structure for the complex of our best inhibitor bound to Chk1 was solved, indicating that it binds to an allosteric site approximately 13A from the ATP binding site. Preliminary data is presented for several of these compounds.
  Bioorganic & medicinal chemistry letters 01/2009; 19(4):1240-4. · 2.65 Impact Factor
• Article: Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors.

  Edward J Brnardic, Robert M Garbaccio, Mark E Fraley, Edward S Tasber, Justin T Steen, Kenneth L Arrington, Vadim Y Dudkin, George D Hartman, Steven M Stirdivant, Bob A Drakas, [......], Weikang Tao, Stephen C Beck, Xianzhi Mao, Robert B Lobell, Laura Sepp-Lorenzino, Youwei Yan, Mari Ikuta, Sanjeev K Munshi, Lawrence C Kuo, Constantine Kreatsoulas
  [show abstract] [hide abstract]
  ABSTRACT: The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC(50)=3.1 nM).
  Bioorganic & Medicinal Chemistry Letters 12/2007; 17(21):5989-94. · 2.55 Impact Factor
• Article: Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.

  Robert M Garbaccio, Shaei Huang, Edward S Tasber, Mark E Fraley, Youwei Yan, Sanjeev Munshi, Mari Ikuta, Lawrence Kuo, Constanine Kreatsoulas, Steve Stirdivant, [......], Kelly A Hamilton, Carolyn A Buser, James Hardwick, Xianzhi Mao, Stephen C Beck, Marc T Abrams, Weikang Tao, Rob Lobell, Laura Sepp-Lorenzino, George D Hartman
  [show abstract] [hide abstract]
  ABSTRACT: From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.
  Bioorganic & Medicinal Chemistry Letters 12/2007; 17(22):6280-5. · 2.55 Impact Factor
• Article: Kinesin spindle protein (KSP) inhibitors. Part 7: Design and synthesis of 3,3-disubstituted dihydropyrazolobenzoxazines as potent inhibitors of the mitotic kinesin KSP.

  Robert M Garbaccio, Edward S Tasber, Lou Anne Neilson, Paul J Coleman, Mark E Fraley, Christy Olson, Jeff Bergman, Maricel Torrent, Carolyn A Buser, Keith Rickert, [......], Lawrence C Kuo, Chunze Li, Thomayant Prueksaritanont, Carmen Fernandez-Metzler, Elizabeth A Mahan, Donald E Slaughter, Joseph J Salata, Nancy E Kohl, Hans E Huber, George D Hartman
  [show abstract] [hide abstract]
  ABSTRACT: Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.
  Bioorganic & Medicinal Chemistry Letters 11/2007; 17(20):5671-6. · 2.55 Impact Factor
• Article: Kinesin spindle protein (KSP) inhibitors. Part 6: Design and synthesis of 3,5-diaryl-4,5-dihydropyrazole amides as potent inhibitors of the mitotic kinesin KSP.

  Paul J Coleman, John D Schreier, Christopher D Cox, Mark E Fraley, Robert M Garbaccio, Carolyn A Buser, Eileen S Walsh, Kelly Hamilton, Robert B Lobell, Keith Rickert, [......], Joseph P Davide, Nancy E Kohl, Youwei Yan, Lawrence Kuo, Thomayant Prueksaritanont, Chunze Li, Elizabeth A Mahan, Carmen Fernandez-Metzler, Joseph J Salata, George D Hartman
  [show abstract] [hide abstract]
  ABSTRACT: 3,5-diaryl-4,5-dihydropyrazoles were discovered to be potent KSP inhibitors with excellent in vivo potency. These enzyme inhibitors possess desirable physical properties that can be readily modified by incorporation of a weakly basic amine. Careful adjustment of amine basicity was essential for preserving cellular potency in a multidrug resistant cell line while maintaining good aqueous solubility.
  Bioorganic & Medicinal Chemistry Letters 11/2007; 17(19):5390-5. · 2.55 Impact Factor
• Article: Kinesin spindle protein (KSP) inhibitors. Part V: discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by beta-fluorination to overcome cellular efflux by P-glycoprotein.

  Christopher D Cox, Michael J Breslin, David B Whitman, Paul J Coleman, Robert M Garbaccio, Mark E Fraley, Matthew M Zrada, Carolyn A Buser, Eileen S Walsh, Kelly Hamilton, Robert B Lobell, Weikang Tao, Marc T Abrams, Vicki J South, Hans E Huber, Nancy E Kohl, George D Hartman
  [show abstract] [hide abstract]
  ABSTRACT: Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs.
  Bioorganic & Medicinal Chemistry Letters 05/2007; 17(10):2697-702. · 2.55 Impact Factor
• Article: An inhibitor of the kinesin spindle protein activates the intrinsic apoptotic pathway independently of p53 and de novo protein synthesis.

  Weikang Tao, Victoria J South, Ronald E Diehl, Joseph P Davide, Laura Sepp-Lorenzino, Mark E Fraley, Kenneth L Arrington, Robert B Lobell
  [show abstract] [hide abstract]
  ABSTRACT: The kinesin spindle protein (KSP), a microtubule motor protein, is essential for the formation of bipolar spindles during mitosis. Inhibition of KSP activates the spindle checkpoint and causes apoptosis. It was shown that prolonged inhibition of KSP activates Bax and caspase-3, which requires a competent spindle checkpoint and couples with mitotic slippage. Here we investigated how Bax is activated by KSP inhibition and the roles of Bax and p53 in KSP inhibitor-induced apoptosis. We demonstrate that small interfering RNA-mediated knockdown of Bax greatly attenuates KSP inhibitor-induced apoptosis and that Bax activation is upstream of caspase activation. This indicates that Bax mediates the lethality of KSP inhibitors and that KSP inhibition provokes apoptosis via the intrinsic apoptotic pathway where Bax activation is prior to caspase activation. Although the BH3-only protein Puma is induced after mitotic slippage, suppression of de novo protein synthesis that abrogates Puma induction does not block activation of Bax or caspase-3, indicating that Bax activation is triggered by a posttranslational event. Comparison of KSP inhibitor-induced apoptosis between matched cell lines containing either functional or deficient p53 reveals that inhibition of KSP induces apoptosis independently of p53 and that p53 is dispensable for spindle checkpoint function. Thus, KSP inhibitors should be active in p53-deficient tumors.
  Molecular and Cellular Biology 02/2007; 27(2):689-98. · 5.53 Impact Factor
• Article: 3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.

  Mark E Fraley, Justin T Steen, Edward J Brnardic, Kenneth L Arrington, Keith L Spencer, Barbara A Hanney, Yuntae Kim, George D Hartman, Steven M Stirdivant, Bob A Drakas, [......], Weikang Tao, Stephen C Beck, Xianzhi Mao, Robert B Lobell, Laura Sepp-Lorenzino, Youwei Yan, Mari Ikuta, Sanjeev K Munshi, Lawrence C Kuo, Constantine Kreatsoulas
  [show abstract] [hide abstract]
  ABSTRACT: The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC(50)=0.30nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.
  Bioorganic & Medicinal Chemistry Letters 01/2007; 16(23):6049-53. · 2.55 Impact Factor
• Article: Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.

  Shaei Huang, Robert M Garbaccio, Mark E Fraley, Justin Steen, Constantine Kreatsoulas, George Hartman, Steve Stirdivant, Bob Drakas, Keith Rickert, Eileen Walsh, [......], Rob Lobell, Laura Sepp-Lorenzino, Youwei Yan, Mari Ikuta, Joan Zugay Murphy, Vinod Sardana, Sanjeev Munshi, Lawrence Kuo, Michael Reilly, Elizabeth Mahan
  [show abstract] [hide abstract]
  ABSTRACT: Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.
  Bioorganic & Medicinal Chemistry Letters 12/2006; 16(22):5907-12. · 2.55 Impact Factor
• Article: Kinesin spindle protein (KSP) inhibitors. Part 3: synthesis and evaluation of phenolic 2,4-diaryl-2,5-dihydropyrroles with reduced hERG binding and employment of a phosphate prodrug strategy for aqueous solubility.

  Robert M Garbaccio, Mark E Fraley, Edward S Tasber, Christy M Olson, William F Hoffman, Kenneth L Arrington, Maricel Torrent, Carolyn A Buser, Eileen S Walsh, Kelly Hamilton, [......], Vicki J South, Youwei Yan, Lawrence C Kuo, Thomayant Prueksaritanont, Donald E Slaughter, Cathy Shu, David C Heimbrook, Nancy E Kohl, Hans E Huber, George D Hartman
  [show abstract] [hide abstract]
  ABSTRACT: 2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy.
  Bioorganic & Medicinal Chemistry Letters 05/2006; 16(7):1780-3. · 2.55 Impact Factor
• Article: Kinesin spindle protein (KSP) inhibitors. Part 2: the design, synthesis, and characterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP.

  Mark E Fraley, Robert M Garbaccio, Kenneth L Arrington, William F Hoffman, Edward S Tasber, Paul J Coleman, Carolyn A Buser, Eileen S Walsh, Kelly Hamilton, Christine Fernandes, [......], Victoria J South, Youwei Yan, Lawrence C Kuo, Thomayant Prueksaritanont, Cathy Shu, Maricel Torrent, David C Heimbrook, Nancy E Kohl, Hans E Huber, George D Hartman
  [show abstract] [hide abstract]
  ABSTRACT: The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC(50)s<10nM. Ancillary hERG activity was evaluated for this series of inhibitors.
  Bioorganic & Medicinal Chemistry Letters 04/2006; 16(7):1775-9. · 2.55 Impact Factor
• Article: Inhibitors of the mitotic kinesin spindle protein

  Paul J Coleman, Mark E Fraley
  [show abstract] [hide abstract]
  ABSTRACT: Small molecule inhibitors of kinesin spindle protein (KSP), a kinesin essential to mitotic spindle formation, arrest cell cycle progression and the proliferation of tumour cells in vitro and in vivo, and thus demonstrate potential as novel antimitotic agents. Recently, KSP inhibitors of wide structural diversity have appeared in the patent literature. This review covers issued patents and patent applications that disclose novel small molecule inhibitors of the mitotic kinesin KSP that appeared between 2001 and July 2004.
  02/2005; 14(12):1659-1667.
• Article: Property-based design of KDR kinase inhibitors.

  Mark E Fraley, William F Hoffman, Kenneth L Arrington, Randy W Hungate, George D Hartman, Rosemary C McFall, Kathleen E Coll, Keith Rickert, Kenneth A Thomas, Georgia B McGaughey
  [show abstract] [hide abstract]
  ABSTRACT: Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
  Current Medicinal Chemistry 04/2004; 11(6):709-19. · 4.86 Impact Factor
• Article: Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF-receptor KDR.

  Zhicai Wu, Mark E Fraley, Mark T Bilodeau, Mildred L Kaufman, Edward S Tasber, Adrienne E Balitza, George D Hartman, Kathleen E Coll, Keith Rickert, Jennifer Shipman, Bin Shi, Laura Sepp-Lorenzino, Kenneth A Thomas
  [show abstract] [hide abstract]
  ABSTRACT: 3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class of KDR kinase inhibitors. A variety of imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were identified with good aqueous solubility.
  Bioorganic & Medicinal Chemistry Letters 03/2004; 14(4):909-12. · 2.55 Impact Factor