Novel indolylindazolylmaleimides as inhibitors of protein kinase C-β: Synthesis, biological activity, and cardiovascular safety

Journal of Medicinal Chemistry

Volumn 48, Issue 6, 2005, Pages 1725-1728

  Zhang, Han Cheng ^a   Derian, Claudia K ^a   McComsey, David F ^a   White, Kimberly B ^a   Ye, Hong ^a   Hecker, Leonard R ^a   Li, Jian ^a   Addo, Michael F ^a   Croll, Diane ^a   Eckardt, Annette J ^a   Smith, Charles E ^a   Li, Quan ^a   Cheung, Wai Man ^a   Conway, Bruce R ^b   Emanuel, Stuart ^b   Demarest, Keith T ^b   Andrade Gordon, Patricia ^a   Damiano, Bruce P ^a   Maryanoff, Bruce E ^a  

^a Drug Discovery   (United States)

^b Drug Discovery Raritan   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CASEIN KINASE; CYCLIN DEPENDENT KINASE; EPIDERMAL GROWTH FACTOR RECEPTOR; INDOLYLINDAZOLYLMALEIMIDES; INSULIN RECEPTOR KINASE; INTERLEUKIN 8; MITOGEN ACTIVATED PROTEIN KINASE 1; PHORBOL 13 ACETATE 12 MYRISTATE; PLATELET DERIVED GROWTH FACTOR RECEPTOR; POTASSIUM CHANNEL HERG; PROTEIN KINASE C BETA; PROTEIN KINASE INHIBITOR; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR;

ARTICLE; BINDING AFFINITY; BIOLOGICAL ACTIVITY; CHEMICAL STRUCTURE; COLUMN CHROMATOGRAPHY; ELECTROCARDIOGRAM; ENZYME INHIBITION; GUINEA PIG; HEART VENTRICLE ARRHYTHMIA; HEART VENTRICLE FIBRILLATION; HUMAN; HUMAN CELL; ION CURRENT; NONHUMAN; PATCH CLAMP; QT INTERVAL; RISK ASSESSMENT; SAFETY; SYNTHESIS;

ANIMALS; CELL LINE; ETHER-A-GO-GO POTASSIUM CHANNELS; GLYCOGEN SYNTHASE KINASE 3; GUINEA PIGS; HUMANS; INDAZOLES; INDOLES; INTERLEUKIN-8; ISOENZYMES; LONG QT SYNDROME; MALEIMIDES; MODELS, MOLECULAR; PATCH-CLAMP TECHNIQUES; POTASSIUM CHANNEL BLOCKERS; POTASSIUM CHANNELS, VOLTAGE-GATED; PROTEIN KINASE C; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 20144379769     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049478u     Document Type: Article

References (28)

1. (a) Garcia-Echeverria, C.; Traxler, P.; Evans, D. B. ATP site-directed competitive and irreversible inhibitors of protein kinases. Med. Res. Rev. 2000, 20, 28-57.
2. (b) Sridhar, R.; Hanson-Painton, O.; Cooper, D. R. Protein kinases as therapeutic targets. Pharm. Res. 2000, 17, 1345-1353.
3. Noble, M. E. M.; Endicott, J. A.; Johnson, L. N. Protein kinase inhibitors: insights into drug design from structure. Science 2004, 303, 1800-1805.
4. There are 11 PKC isozymes (conventional, α, βI, βII, and γ; novel, δ, ε, L/η, θ, and μ; atypical, ζ and ι/λ). PKC enzymes regulate vascular tone, permeability, and proliferation, and they are involved in cardiovascular disease, cancer, ischemia, inflammation, and CNS disorders. Goekjian, P. G.; Jirousek, M. R. Protein kinase C in the treatment of disease: signal transduction pathways, inhibitors, and agents in development. Curr. Med. Chem. 1999, 6, 877-903.
5. Shen, G. X. Selective protein kinase C inhibitors and their applications. Curr. Drug Targets: Cardiovasc. Haematol. Disord. 2003, 3, 301-307.
6. (a) Way, K. J.; Katai, N.; King, G. L. Protein kinase C and the development of diabetic vascular complications. Diabetes Med. 2001, 18, 945-959.
7. (b) Bullock, W. H.; Magnuson, S. R.; Choi, S.; Gunn, D. E.; Rudolph, J. Prospects for kinase activity modulators in the treatment of diabetes and diabetic complications. Curr. Top. Med. Chem. 2002, 2, 915-938.
8. (a) Ishii, H.; Jirousek, M. R.; Koya, D.; Takagi, C.; Xia, P. Clermont, A. Bursell, S.-E.; Kern, T. S.; Ballas, L. M.; Health, L. E.; Stramm, L. E.; Feener, E. P.; King, G. L. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC-β inhibitor. Science 1896, 272, 728-731.
9. (b) Jirousek, M. R.; Gillig, J. R.; Gonzalez, C. M.; Heath, W. F.; McDonald, J. H., III; Neel, D. A.; Rito, C. J.; Singh, U.; Stramm, L. E.; Melikian-Badalian A.; Baevsky, M.; Ballas, L. M.; Hall, S. E.; Winneroski, L. L.; Faul, M. M. (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21- dimetheno-1H,13H-dibenzo[e,k]-pyrrolo[3,4-h][1,4,13]-oxadiazacyclohexadecene-1, 3(2H)-dione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase Cβ. J. Med. Chem. 1996, 39, 2664-2671.
10. (c) Sorbera, L. A.; Silvestre, J.; Rabasseda, X.; Castaner, J. LY-333531 mesylate hydrate: symptomatic antidiabetic; protein kinase C inhibitor. Drugs Future 2000, 25, 1017-1026.
11. (d) A follow-up series of acyclic PKC-β inhibitors has been reported: Faul, M. M.; Gillig, J. R.; Jirousek, M. R.; Ballas, L. M.; Schotten, T.; Kahl, A.; Mohr, M. Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCβ. Bioorg. Med. Chem. Lett. 2003, 13, 1857-1859.
12. Several nonselective PKC inhibitors, such as staurosporine analogues UCN-01 and CGP-41251, are in anticancer clinical trials. Goekjian, P. G.; Jirousek, M. R. Protein kinase C inhibitors as novel anticancer drugs. Expert Opin. Invest. Drugs 2001, 10, 2117-2140.
13. Zhang, H.-C.; White, K. B.; Ye, H.; McComsey, D. F.; Derian, C. K.; Addo, M. F.; Andrade-Gordon, P.; Eckardt, A. J.; Conway, B. R.; Westover, L.; Xu, J. Z.; Look, R.; Demarest, K. T.; Emanuel, S.; Maryanoff, B. E. Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3. Bioorg. Med. Chem. Lett. 2003, 13, 3049-5053.
14. (a) Kuo, G.-H.; Prouty, C.; DeAngelis, A.; Shen, L.; O'Neill, D. J.; Shah, C.; Connolly, P. J.; Murray, W. V.; Conway, B. R.; Cheung, P.; Westover, L.; Xu, J. Z.; Look, R. A.; Demarest, K. T.; Emanuel, S.; Middleton, S. A.; Jolliffe, L.; Beavers, M. P.; Chen, X. Synthesis and discovery of macrocyclic polyoxygenated bis-7-azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-3β inhibitors. J. Med. Chem. 2003, 46, 4021-4031.
15. (b) Zhang, H.-C.; Ye, H.; Conway, B. R.; Derian, C. K.; Addo, M. F.; Kuo, G.-H.; Hecker, L. R.; Croll, D. R.; Li, J.; Westover, L.; Xu, J. Z.; Look, R.; Demarest, K. T.; Andrade-Gordon, P.; Damiano, B. P.; Maryanoff, B. E. 3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3. Bioorg. Med. Chem. Lett. 2004, 14, 3245-3250.
16. Other maleimide-type derivatives have been reported to potently inhibit GSK-3β: Hers, I.; Tavare, J. M.; Denton, R. M. The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity. FEBS Lett. 1999, 460, 433-436. Coghlan, M. P.; Culbert, A. A.; Cross, D. A. E.; Corcoran, S. L.; Yates, J. W.; Pearce, N. J.; Rausch, O. L.; Murphy, G. J.; Carter, P. S.; Cox, L. R.; Mills, D.; Brown, M. J.; Haigh, D.; Ward, R. W.; Smith, D. G.; Murray, K. J.; Reith, A. D.; Holder, J. C. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol. 2000, 7, 793-803. Smith, D. G.; Buffet, M.; Fenwick, A. E.; Haigh, D.; Ife, R. J.; Saunders, M.; Slingsby, B. P.; Stacey, R.; Ward, R. W. 3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorg. Med. Chem. Lett. 2001, 11, 635-639.
17. Other maleimide-type derivatives have been reported to potently inhibit GSK-3β: Hers, I.; Tavare, J. M.; Denton, R. M. The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity. FEBS Lett. 1999, 460, 433-436. Coghlan, M. P.; Culbert, A. A.; Cross, D. A. E.; Corcoran, S. L.; Yates, J. W.; Pearce, N. J.; Rausch, O. L.; Murphy, G. J.; Carter, P. S.; Cox, L. R.; Mills, D.; Brown, M. J.; Haigh, D.; Ward, R. W.; Smith, D. G.; Murray, K. J.; Reith, A. D.; Holder, J. C. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol. 2000, 7, 793-803. Smith, D. G.; Buffet, M.; Fenwick, A. E.; Haigh, D.; Ife, R. J.; Saunders, M.; Slingsby, B. P.; Stacey, R.; Ward, R. W. 3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorg. Med. Chem. Lett. 2001, 11, 635-639.
18. Other maleimide-type derivatives have been reported to potently inhibit GSK-3β: Hers, I.; Tavare, J. M.; Denton, R. M. The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity. FEBS Lett. 1999, 460, 433-436. Coghlan, M. P.; Culbert, A. A.; Cross, D. A. E.; Corcoran, S. L.; Yates, J. W.; Pearce, N. J.; Rausch, O. L.; Murphy, G. J.; Carter, P. S.; Cox, L. R.; Mills, D.; Brown, M. J.; Haigh, D.; Ward, R. W.; Smith, D. G.; Murray, K. J.; Reith, A. D.; Holder, J. C. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol. 2000, 7, 793-803. Smith, D. G.; Buffet, M.; Fenwick, A. E.; Haigh, D.; Ife, R. J.; Saunders, M.; Slingsby, B. P.; Stacey, R.; Ward, R. W. 3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorg. Med. Chem. Lett. 2001, 11, 635-639.
19. Mylari, B. L.; Zembrowski, W. J.; Beyer, T. A.; Aldinger, C. E.; Siegel, T. W. Orally active aldose reductase inhibitors: inda zoleacetic, oxopyridazineacetic, and oxopyridopyridazineacetic acid derivatives. J. Med. Chem. 1992, 35, 2155-2162.
20. Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. A new one step synthesis of maleimides by condensation of glyoxylate esters with acetamides. Tetrahedron Lett. 1899, 40, 1109-1112.
21. LigandFit: Cerius2, version 4.9; Accelrys Inc., San Diego CA, 2003.
22. Sanchez, R.; Sali, A. Comparative protein structure modeling. Introduction and practical examples with modeler. Methods Mol. Biol. 2000, 143, 97-129.
23. Bertrand, J. A.; Thieffine, S.; Vulpetti, A.; Cristiani, C.; Valsasina, B.; Knapp, S.; Kalisz, H. M.; Flocco, M. Structural characterization of the GSK-3β active site using selective and non-selective ATP-mimetic inhibitors. J. Mol. Biol. 2003, 333, 393-407.
24. Viskin, S. Long QT syndromes and torsade de pointes. Lancet 1989, 354, 1625-1633.
25. Mitcheson, J. S.; Chen, J.; Lin, M.; Culberson, C.; Sanguinetti, M. C. A structural basis for drug-induced long QT syndrome. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 12329-12333.
26. Gonzalez, J. E.; Oades, K.; Leychkis, Y.; Harootunian, A.; Negulescu, P. A. Cell-based assays and instrumentation for screening ion-channel targets. Drug Discovery Today 1999, 4, 431-439.
27. Lacerda, A. E.; Kramer, J.; Shen, K. Z.; Thomas, D.; Brown, A. M. Comparison of block among cloned cardiac potassium channels by non-antiarrhythmic drugs. Eur. Heart J. Suppl. 2001, 3, K23-K30.
28. Grant, E. R.; Errico, M. A.; Emanuel, S. L.; Benjamin, D.; McMillian, M. K.; Wadsworth, S. A.; Zivin, R. A.; Zhong, Z. Protection against glutamate toxicity through inhibition of the p44/42 mitogen-activated protein kinase pathway in neuronally differentiated P19 cells. Biochem. Pharmacol. 2001, 62, 283-296.