Discovery of 3,3′-(2,4-diaminopteridine-6,7-diyl)diphenol as an isozyme-selective inhibitor of PI3K for the treatment of ischemia reperfusion injury associated with myocardial infarction

Journal of Medicinal Chemistry

Volumn 50, Issue 18, 2007, Pages 4279-4294

  Palanki, Moorthy S S ^a   Dneprovskaia, Elena ^a   Doukas, John ^a   Fine, Richard M ^b   Hood, John ^a   Kang, Xinshan ^b   Lohse, Dan ^a   Martin, Michael ^a   Noronha, Glenn ^a   Soll, Richard M ^a   Wrasidlo, Wolfgang ^a   Yee, Shiyin ^a   Zhu, Hong ^a  

^a TargeGen Inc   (United States)

^b BioPredict Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; 3,3' (2,4 DIAMINOPTERIDINE 6,7 DIYL)DIPHENOL; 6,7 BIS(3 HYDROXYPHENYL)PTERIDINE 2,4 DIAMINE; ADENOSINE TRIPHOSPHATE; AMINOPYRIDINE; AMINOPYRIMIDINE; DIAMINOPTERIDINE DIPHENOL; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PTERIDINE; PYRAZINE DERIVATIVE; PYRIDOPYRAZINE DERIVATIVE; PYRIMIDINE DERIVATIVE; QUERCETIN; STAUROSPORINE; UNCLASSIFIED DRUG; VASCULOTROPIN; WORTMANNIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BINDING AFFINITY; CHEMICAL MODIFICATION; CONTROLLED STUDY; DISEASE ASSOCIATION; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HEART INFARCTION; HUMAN; HUMAN CELL; HUMAN TISSUE; IN VIVO STUDY; MALE; NONHUMAN; RAT; REACTION OPTIMIZATION; REPERFUSION INJURY; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; ANTIGENS, CD; CADHERINS; CAPILLARY PERMEABILITY; CELL PROLIFERATION; CELLS, CULTURED; ENDOTHELIAL CELLS; HUMANS; ISOENZYMES; MALE; MODELS, MOLECULAR; MYOCARDIAL INFARCTION; MYOCARDIAL REPERFUSION INJURY; PHENOLS; PHOSPHORYLATION; PTERIDINES; PYRAZINES; PYRIDINES; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; UMBILICAL VEINS; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 34548473308     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm051056c     Document Type: Article

References (75)

1. (a) Senger, D. R.; Galli, S. J.; Dvorak, A. M.; Perruzzi, C. A.; Harvey, V. S.; Dvorak, H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983, 219 983-985.
2. Pratt, D. J.; Endicott, J. A.; Noble, M. E. The role of structure in kinase-targeted inhibitor design. Curr. Opin. Drug Discovery Dev 2004, 7, 428-436.
3. Mecklenbrauker, I.; Kalled, S. L.; Leitges, M.; Mackay, F.; Tarakhovsky, A. Regulation of B-cell survival by BAFF-dependent PKCδ mediated nuclear signaling. Nature 2004, 431, 456-461.
4. Kinzel, V.; Mueller, G. C. Phosphorylation of surface proteins of HeLa cells using an exogenous protein kinase and (gamma-32P)-ATP. Biochim. Biophys. Acta 1973, 322, 337-351.
5. Dancey, J.; Sausville, E. A. Issues and progress with protein kinase inhibitors for cancer treatment. Nat. Rev. Drug Discovery 2003, 2, 296-313.
6. Ishizawar, R.; Parsons, S. J. c-Src and cooperating partners in human cancer. Cancer Cell. 2004, 6, 209-214.
7. Olmsted, J. B.; Borisy, G. G. Microtubules. Annu. Rev. Biochem. 1973, 42, 507-540.
8. Bitensky, M. W.; Gorman, R. E. Cellular responses to cyclic AMP. Prog. Biophys. Mol. Biol. 1973, 26, 409-461.
9. Shin, N. Y.; Dise, R. S.; Schneider-Mergener, J.; Ritchie, M. D.; Kilkenny, D. M.; Hanks, S. K. Subsets of the major phosphorylation sites in Crk-associated substrate (CAS) are sufficient to promote cell migration. J. Biol. Chem. 2004, 279, 38331-38337.
10. Frey, M. R.; Golovin, A.; Polk, D. B. Epidermal growth factor-stimulated intestinal epithelial cell migration requires Scr family kinase-dependent p38 MAPK signaling. J. Biol. Chem. 2004, 279, 44513-44521.
11. McConkey, D. J.; Hartzell, P.; Jondal, M.; Orrenius, S. Inhibition of DNA fragmentation in thymocytes and isolated thymocyte nuclei by agents that stimulate protein kinase C. J. Biol. Chem. 1989, 264, 13399-13402.
12. Lee, M.; Kim, J. Y.; Koh, W. S. Apoptotic effect of PP2 a Src tyrosine kinase inhibitor, in murine B cell leukemia. J. Cell Biochem. 2004, 93, 629-638.
13. Gruber, C.; Henkel, M.; Budach, W.; Belka, C.; Jendrossek, V. Involvement of tyrosine kinase p56/Lck in apoptosis induction by anticancer drugs. Biochem. Pharmacol. 2004, 67, 1859-1872.
14. Park, S. S.; Eom, Y. W.; Kim, E. H.; Lee, J. H.; Min do, S.; Kim, S.; Choi, K. S. Involvement of c-Src kinase in the regulation of TGF-betal-induced apoptosis. Oncogene 2004, 23, 6272-6281.
15. Shelton, J. G.; Moye, P. W.; Steelman, L. S.; Blalock, W. L.; Lee, J. T.; Franklin, R. A.; McMahon, M.; McCubrey, J. A. Differential effects of kinase cascade inhibitors on neoplastic and cytokine-mediated cell proliferation. Leukemia 2003, 17, 1765-1782.
16. Gschwind, A.; Fischer, O. M.; Ullrich, A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer 2004, 4, 361-370.
17. Cines, D. B.; Pollak, E. S.; Buck, C. A.; Loscalzo, J.; Zimmerman, G. A.; McEver, R. P.; Pober, J. S.; Wick, T. M.; Konkle, B. A.; Schwartz, B. S.; Barnathan, E. S.; McCrae, K. R.; Hug, B. A.; Schmidt, A. M.; Stern, D. M. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998, 91, 3527-3561.
18. Weis, S.; Shintani, S.; Weber, A.; Kirchmair, R.; Wood, M.; Cravens, A.; McSharry, H.; Iwakura, A.; Yoon, Y. S.; Himes, N.; Burstein, D.; Doukas, J.; Soll, R.; Losordo, D.; Cheresh, D. Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J. Clin. Invest. 2004, 113, 885-894.
19. Paul, R.; Zhang, Z. G.; Eliceiri, B. P.; Jiang, Q.; Boccia, A. D.; Zhang, R. L.; Chopp, M.; Cheresh, D. Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat. Med. 2001, 7, 222-227.
20. Hanke, J. H.; Gardner, J. P.; Dow, R. L.; Changelian, P. S.; Brissette, W. H.; Weringer, E. J.; Pollok, B. A.; Connelly, P. A. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem. 1996, 271, 695-701.
21. Warmuth, M.; Damoiseaux, R.; Liu, Y.; Fabbro, D.; Gray, N. Src family kinases: potential targets for the treatment of human cancer and leukemia. Curr. Pharm. Des. 2003, 9, 2043-2059.
22. Tsygankov, A. Y.; Shore, S. K. Src: regulation, role in human carcinogenesis and pharmacological inhibitors. Curr. Pharm. Des. 2004, 10, 1745-1756.
23. Levin, V. A. Basis and importance of Src as a target in cancer. Cancer Treat. Res. 2004, 119, 89-119.
24. Creemer, L. C.; Kirst, H. A.; Vlahos, C. J.; Schultz, R. M. Synthesis and in Vitro Evaluation of New Wortmannin Esters: Potent Inhibitors of Phosphatidylinositol 3-Kinase. J. Med. Chem. 1996, 39, 5021-5024.
25. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-Kinase Akt pathway in human cancer. Nat. Rev. Cancer 2002, 2, 489-501.
26. Stein, R. C.; Waterfield, M. D. PI3-kinase inhibition: a target for drug development? Mol. Med. Today 2000, 6, 347-357.
27. Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.; Hawkins, P. T.; Wymann, M. P.; Williams, R. L. Structural determinants of phosphoinositide 3-kinase inhibition by Wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol. Cell 2000, 6, 909-919.
28. Zhu, T.; Gu, J.; Yu, K. Lucas, J.; Cai, P.; Tsao, R.; Gong, Y.; Li, F.; Chaudhary, I.; Desai, P. Ruppen, M.; Fawzi, M.; Gibbons, J.; Ayral-Kaloustian, S.; Skotnicki, J.; Mansour, T.; Zask, A.; Pegylated Wortmannin and 17-Hydroxywortmannin Conjugates as Phosphoinositide 3-Kinase Inhibitors Active in Human Tumor Xenograft Models. J. Med. Chem. 2006, 49, 1373-1378.
29. Gammill, R. B.; Judge, T. M.; Morris, J. Preparation of antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones. PCT Int. Appl. WO9119707, 1991.
30. Gogliotti, R. D.; Muccioli, K. L.; Para, K. S.; Visnick, M. Preparation of benzoxazines and related compounds as inhibitors of PI3Ks. PCT Int. Appl. WO2004056820, 2004.
31. Connolly, M. K.; Cogliotti, R. D.; Hurt, C. R.; Reichard, G. A.; Visnick, M. Preparation of halo-substituted N-tetrazolylbenzo[b]- thiophenecarboxamides with P13K inhibitory activity as therapeutic agents. PCT Int. Appl. WO2005023800, 2005.
32. Gogliotti, R. D.; Lee, H. T.; Sexton, K. E.; Visnick, M. Preparation of tetrazolyl benzofurancarboxamides as phosphoinositide-3-kinase (PI3K) inhibitors for the treatment of cancer, inflammatory and cardiovascular diseases. PCT Int. Appl. WO2004108709, 2004.
33. Connolly, M. K.; Gogliotti, R. D.; Plummer, M. S.; Visnick, M. Preparation of morpholinyl-pyrimidine derivatives as inhibitors of phosphoinositide-3-kinases. PCT Int. Appl. WO2005042519, 2005.
34. Shimada, M.; Murata, T.; Fuchikami, K.; Tsujishita, H.; Omori, N.; Kato, I.; Miura, M.; Urbahns, K.; Gantner, F.; Bacon, K. Preparation of fused azole-pyrimidine derivatives as PI3K inhibitors with therapeutic uses. PCT Int. Appl. WO2004029055, 2004.
35. Bagli, E.; Stefaniotou, M.; Morbidelli, L.; Ziche, M.; Psillas, K.; Murphy, C.; Fotsis, T. Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3′-kinase activity. Cancer Res. 2004, 64, 7936-7946.
36. Wang, S.; Dusting, G. J.; May, C. N.; Woodman, O. L. 3′4′- Dihydroxyflavonol reduces infarct size and injury associated with myocardial ischaemia and reperfusion in sheep. Br J. Pharmacol. 2004, 142, 443-452.
37. Suzuki, M.; Tabuchi, M.; Ikeda, M.; Umegaki, K.; Tomita, T. Protective effects of green tea catechins on cerebral ischemic damage. Med. Sci. Monit. 2004, 10, 166-174.
38. Kiziltepe, U.; Turan, N. N.; Han, U.; Ulus, A. T.; Akar, F. Resveratrol, a red wine polyphenol, protects spinal cord from ischemia-reperfusion injury. J. Vasc. Surg. 2004, 40, 138-145.
39. Choi, Y. B.; Kim, Y. I.; Lee, L. S.; Kim, B. S.; Kim, D. J. Protective effect of epigallocatechin gallate on brain damage after transient middle cerebral artery occlusion in rats. Brain Res. 2004, 1019, 47-54.
40. Li, X. L.; Li, Y. Q.; Yan, W. M.; Li, H. Y.; Xu, H.; Zheng, X. X.; Guo, D. W.; Tang, L. K. A study of the cardioprotective effect of breviscapine during hypoxia of cardiomyocytes. Planta Med. 2004, 70, 1039-1044.
41. Graboyes, H.; Day, A. R. Metabolite Analogs. VIII. Syntheses of some imidazolopyridines and pyridotriazoles. J. Am. Chem. Soc. 1957, 79, 6421-6426.
42. Ohmori J.; Kubota, H.; Shimizu-Sasamata, M.; Okada, M.; Sakamoto, S. Novel α-amino-3-hydroxy-5-methylisoxazole-4-propionate recep3 tor antagonists: synthesis and structure-activity relationships of 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2, 3-b]pyrazinedi-one and related compounds. J. Med. Chem. 1996, 39, 1331-1338.
43. (a) Taylor, E. C.; Perlman, K. L.; Kim, Y. H.; Sword, I. P.; Jacobi, P. A. Pteridines. XXIX. An Unequivocal route to 2,4-diamino-6-substituted pteridines. J. Am. Chem. Soc. 1973, 95, 6413-6418.
44. (b) Taylor, E. C.; Ray, P. S. Pteridines. 51. A new and unequivocal route to C-6 carbon-substituted pterins and pteridines. J. Org. Chem. 1987, 52, 3997-4000.
45. (a) De Meester, J. W. G.; van der Plas, H. C. The oxidation of 6-and 7-Aryl-4(3H)-pteridinones by immobilized arthrobacter M-4 cells containing xanthine oxidase. J. Heterocycl. Chem. 1987, 24, 441-452.
46. (b) Campillo, N.; Goya, P.; Paez, J. A. Novel arylpyrazino-[2,3-c] [1,2,6]thiadiazine 2,2-dioxides as platelet aggregation inhibitors. 2. Optimization by quantitative structure-activity relationships. J. Med. Chem. 1999, 42, 3279-3288.
47. (c) Ishikawa, T. Product class 21: pteridines and related structures. Sci. Synth. 2004, 16, 1291-1335.
48. (a) Yamamoto, H.; Hutzenlaub, W.; Pfleiderer, W. Synthesis and properties of pterin- and 2,6-diamino-pteridine-mono and di-N-oxides. Chem. Ber. 1973, 106, 3175-3193.
49. (b) Taghavi-Moghadam, S.; Pfleiderer, W. A new general and regioselective method for the synthesis of 2,4-disubstituted 4-amino-pteridines. Tetrahedron Lett. 1997, 39, 6835-6836.
50. Kim, Y.; Kang, Y.; Baek, D. Oxidative synthesis of benzoylpteridines from benzylpteridines by potassium permanganate. Bull. Korean Chem. Soc. 2001, 22, 141-144.
51. Gavard, J.; Gutkind, J. S. VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat. Cell. Biol. 2006, 8, 1223-1234.
52. Brkovic, A.; Sirois, M. G. Vascular permeability induced by VEGF family members in vivo: role of endogenous PAF and NO synthesis. J. Cell Biochem. 2007, 100, 727-737.
53. Bateman, R. M.; Tokunaga C.; Kareco, T.; Dorscheid, D. R.; Walley, K. R. Myocardial hypoxia-inducible HIF-1α, VEGF and GLUT1 gene expression is associated with microvascular and ICAM-1 heterogeneity during endotoxemia. Am J. Physiol Heart Circ. Physiol. 2007, 293, H448-456.
54. Hasebe, Y.; Egawa, K.; Yamazaki, Y.; Kunimoto, S.; Hirai, Y.; Ida, Y.; Nose, K. Specific inhibition of hypoxia-inducible factor (HIF)-1 alpha activation and of vascular endothelial growth factor (VEGF) production by flavonoids. Biol. Pharm. Bull 2003, 26, 1379-1383.
55. Duarte, J.; Jimenez, R.; O'Valle, F.; Galisteo, M.; Perez-Palencia, R.; Vargas, F.; Perez-Vizcaino, F.; Zarzuelo, A.; Tamargo, J. Protective effects of the flavonoid quercetin in chronic nitric oxide deficient rats. J. Hypertens. 2002, 20, 1843-1854.
56. Yuan, S. Y. Protein kinase signaling in the modulation of microvascular permeability. Vascul. Pharmacol. 2002, 39, 213-223.
57. The antibodies used in this study for Western blotting were from Santa Cruz Biotechnology; catalog no. sc-6548, Santa Cruz, CA (antibody to VE-Cadherin), and Chemicon; catalog no. APT-184, Temecula, CA (Omni-Phos, and pan-phosphorylated proteins).
58. Doukas, J.; Wrasidlo, W.; Noronha, G.; Dneprovskaia, E.; Fine, R.; Weis, S.; Hood, J.; Demaria, A.; Soll, R.; Cheresh, D. Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 19866-71. Briefly, cell proliferation assays was carried out using human umbilical vein EC plated in 96-well cluster plates (5000 cells/well) were cultured in assay medium (containing 0.5% serum and 50 ng/ml VEGF) in the presence or absence of test compounds (10 μM), and cell numbers were quantified by XTT assay (Promega, Madison, WI) after 24, 48, or 72 h later.
59. Kinexus provides antibody microarray services that would examine cell lysates using 377 pan-specific and 273 phospho-site-specific antibodies. The proteomics service provides information on protein expression, phosphorylation, and protein-protein expression from cell lysates. This technique would allow one to examine the kinases that were affected by a compound. The complete details are provided at their web site (www.kinexus.ca). Kinexus technology would allow one to examine numerous pathways. Visit their web site for more information. The concentration of compound 6 was 10 μM in cell assays.
60. Hu, E.; Mueller, E.; Oliviero, S.; Papaioannou, V. E.; Johnson, R.; Spiegelman, B. M. Targeted disruption of the c-Fos gene demonstrates c-Fos-dependent and -independent pathways for gene expression stimulated by growth factors or oncogenes. EMBO J. 1994, 13, 3094-3103.
61. Frohlich, L. G.; Kotsonis, P.; Traub, H.; Taghavi-Moghadam, S.; Al-Masoudi, N.; Hofmann, H.; Strobel, H.; Matter, H.; Pfleiderer, W.; Schmidt, H. H. H. W. Inhibition of neuronal nitric oxide synthase by 4-amino pteridine derivatives: structure-activity relationship of antagonists of (6R)-5,6,7,8-tetrahydrobiopterin Cofactor. J. Med. Chem, 1999, 42, 4108-4121.
62. Doukas, J.; Wrasidlo, W.; Noronha, G.; Dneprovskaia, E.; Fine, R.; Weis, S.; Hood, J.; Demaria, A.; Soll, R.; Cheresh, D. Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 19866-71.
63. Laffargue, M.; Calvez, R.; Finan, P.; Trifilieff, A.; Barbier, M.; Altruda, F.; Hirsch, E.; Wymann, M. P. Phosphoinositide 3-kinase g is an essential amplifier of mast cell function. Immunity 2002, 16, 441-451.
64. 50 determinations. Compound 6 potently inhibited the β, δ, and γ isoforms of PI3K. Apart from the PI3K isoforms, compound 6 also inhibited AAk1, BIKE, CLK1, CLK2, CLK3, PKCμ, RIPK2, and Tie2. This information is provided as supplementary material (Appendix A).
65. DISCOVER, Insight II and the CFF force field are trademarked software offerings from Accelrys Inc., San Diego, CA.
66. Manuscript in preparation.
67. http://clinicaltrials.gov/ct/show/NCT00103350?order=1.
68. YASARA is a trademarked software offering of Yasara Biosciences, Austria.
69. (a) Ferby, I. M.; Waga, I.; Hoshino, M.; Kume, K.; Shimizu, T. Wortmannin inhibits mitogen-activated protein kinase activation by platelet-activating factor through a mechanism independent of p85/p110-type phosphatidylinositol 3-kinase. J. Biol. Chem. 1996, 271 11684-11688.
70. (b) Nakanishi, S.; Kakita, S.; Takahashi, I.; Kawahara, K.; Tsukuda, E.; Sano, T.; Yamada, K.; Yoshida, M.; Kase, H.; Matsuda, Y. Wortmannin, a microbial product inhibitor of myosin light chain kinase. J. Biol. Chem. 1992, 267, 2157-2163.
71. (c) Vanhaesebroeck, B.; Leevers, S. J.; Ahmadi, K.; Timms, J.; Katso, R.; Driscoll, P. C.; Woscholski, R.; Parker, P. J.; Waterfield, M. D. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 2001, 70, 535-602.
72. Camps, M.; Ruckle, T.; Ji, H.; Ardissone, V.; Rintelen, F.; Shaw, J.; Ferrandi, C.; Chabert, C.; Gillieron, C.; Francon, B.; Martin, T.; Gretener, D.; Perrin, D.; Leroy, D.; Vitte, P. A.; Hirsch, E.; Wymann, M. P.; Cirillo, R.; Schwarz, M., K.; Rommel, C. Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat. Med. 2005, 11, 936-943.
73. Poh, T., W.; Pervaiz, S. LY294002 and LY303511 sensitize tumor cells to drug-induced apoptosis via intracellular hydrogen peroxide production independent of the phosphoinositide 3-kinase-Akt pathway. Cancer Res. 2005, 65, 6264-6274.
74. Lesk, A. M. Extraction of well-fitting substructures: root-mean-square deviation and the difference distance matrix. Fold. Des. 1997, 2 (3), S12-4.
75. Duncan, B. S.; Olson, A. J. Shape analysis of molecular surfaces. Biopolymers 1993, 2, 231-238.