Selective p38α inhibitors clinically evaluated for the treatment of chronic inflammatory disorders

Journal of Medicinal Chemistry

Volumn 53, Issue 6, 2010, Pages 2345-2353

  Goldstein, David M ^a   Kuglstatter, Andreas ^a   Lou, Yan ^a   Soth, Michael J ^a  

^a ROCHE BIOSCIENCE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 (2,6 DICHLOROPHENYL) 2 (2,4 DIFLUOROPHENYLTHIO)PYRIMIDO[1,6 B]PYRIDAZIN 6 ONE; ARRY 614; ARRY 797; BMS 582949; BORTEZOMIB; DISEASE MODIFYING ANTIRHEUMATIC DRUG; DORAMAPIMOD; GW 856553; METHOTREXATE; MITOGEN ACTIVATED PROTEIN KINASE P38 ALPHA INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; PAMAPIMOD; PH 797804; PLACEBO; SB 681323; SCIO 469; UNCLASSIFIED DRUG; VX 702; CARBANILAMIDE DERIVATIVE; ENZYME INHIBITOR; INDOLE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE P38; PYRIDONE DERIVATIVE; PYRIMIDINE DERIVATIVE; SCIO-469;

CARDIOVASCULAR DISEASE; CHRONIC INFLAMMATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; CROHN DISEASE; DEPRESSION; DIZZINESS; DRUG EFFICACY; DRUG ERUPTION; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; GASTROINTESTINAL DISEASE; GASTROINTESTINAL SYMPTOM; HEADACHE; HUMAN; INFECTION; LIVER FUNCTION TEST; MUSCULOSKELETAL DISEASE; NAUSEA; NEUROTOXICITY; REVIEW; RHEUMATOID ARTHRITIS; SIDE EFFECT; SKIN DISEASE; UPPER RESPIRATORY TRACT INFECTION; ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; CHRONIC DISEASE; DRUG ANTAGONISM; ENTERITIS; ENZYMOLOGY; METABOLISM; PHASE 2 CLINICAL TRIAL; PROTEIN BINDING; PSORIASIS; TREATMENT OUTCOME; X RAY CRYSTALLOGRAPHY;

ARTHRITIS, RHEUMATOID; CHRONIC DISEASE; CLINICAL TRIALS, PHASE II AS TOPIC; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HUMANS; INDOLES; INFLAMMATORY BOWEL DISEASES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PHENYLUREA COMPOUNDS; PROTEIN BINDING; PSORIASIS; PYRIDONES; PYRIMIDINES; TREATMENT OUTCOME;

EID: 77949808406     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm9012906     Document Type: Review

References (64)

1. Schett, G.; Zwerina, J.; Firestein, G. The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann. Rheum. Dis. 2008, 67, 909-916.
2. Westra, J.; Limburg, P. C. p38 mitogen-activated protein kinase (MAPK) in rheumatoid arthritis. Mini-Rev. Med. Chem. 2006, 6, 867-874.
3. Schett, G.; Stach, C.; Zwerina, J.; Voll, R.; Manger, B. How antirheumatic drugs protect joints from damage in rheumatoid arthritis. Arthritis Rheum. 2008, 58, 2936-2948.
4. Strand, V.; Singh, J. A. Improved health-related quality of life with effective disease-modifying antirheumatic drugs: evidence from randomized controlled trials. Am. J. Manag. Care 2008, 14, 234-254.
5. Hale, K. K.; Trollinger, D.; Rihanek, M.; Manthey, C. L. Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages. J. Immunol. 1999, 162, 4246-4252.
6. Korb, A.; Tohidast-Akrad, M.; Cetin, E.; Axmann, R.; Smolen, J.; Schett, G. Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis. Arthritis Rheum. 2006, 54, 2745-2756.
7. Schett, G.; Tohidast-Akrad, M.; Smolen, J. S.; Schmid, B. J.; Steiner, C. W.; Bitzan, P.; Zenz, P.; Redlich, K.; Xu, Q.; Steiner, G. Activation, differential localization, and regulation of the stressactivated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthritis Rheum. 2000, 43, 2501-2512.
8. Goldstein, D. M.; Gabriel, T. Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development. Curr. Top. Med. Chem. 2005, 5, 1017-1029.
9. Pettus, L. H.; Wurz, R. P. Small molecule p38 MAP kinase inhibitors for the treatment of inflammatory diseases: novel structures and developments during 2006-2008. Curr. Top. Med. Chem. 2008, 8, 1452-1467.
10. Genovese, M. C. Inhibition of p38: has the fat lady sung? Arthritis Rheum. 2009, 60, 317-320.
11. Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science 2002, 298, 1912-1934.
12. Conway, J. G.; McDonald, B.; Parham, J.; Keith, B.; Rusnak, D. W.; Shaw, E.; Jansen, M.; Lin, P.; Payne, A.; Crosby, R. M.; Johnson, J. H.; Frick, L.; Lin, M. H.; Depee, S.; Tadepalli, S.; Votta, B.; James, I.; Fuller, K.; Chambers, T. J.; Kull, F. C.; Chamberlain, S. D.; Hutchins, J. T. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 16078-16083.
13. Karaman, M. W.; Herrgard, S.; Treiber, D. K.; Gallant, P.; Atteridge, C. E.; Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.; Edeen, P. T.; Faraoni, R.; Floyd, M.; Hunt, J. P.; Lockhart, D. J.; Milanov, Z. V.; Morrison, M. J.; Pallares, G.; Patel, H. K.; Pritchard, S.; Wodicka, L. M.; Zarrinkar, P. P. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol. 2008, 26, 127-132.
14. Xia, W.; Mullin, R. J.; Keith, B. R.; Liu, L. H.; Ma, H.; Rusnak, D. W.; Owens, G.; Alligood, K. J.; Spector, N. L. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002, 21, 6255-6263.
15. Cuenda, A.; Rouse, J.; Doza, Y. N.; Meier, R.; Cohen, P.; Gallagher, T. F.; Young, P. R.; Lee, J. C. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 1995, 364, 229-233.
16. Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P. F.; Gilmore, T.; Graham, A. G.; Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S.; Regan, J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat. Struct. Biol. 2002, 9, 268-272.
17. Leftheris, K. Hot topic: p38 kinase inhibitor. Curr. Top. Med. Chem. 2005, 5, 919.
18. Mavunkel, B. J.; Chakravarty, S.; Perumattam, J.; Dugar, S.; Lu, Q.; Liang, X. Preparation of 5-[4-Benzylpiperidinyl(piperazinyl)]-indolecarboxamides as Inhibitors of p38 Kinase. WO2000071535, 2000.
19. Oliver-Shaffer, P.-A.; Snoonian, J. R. Processes for the Preparation of N-Heteroaryl-N-aryl-amines by Reacting an N-Aiyl Carbamic Acid Ester with a Halo-Heteroaryl and Analogous Processes. WO2004072038, 2004.
20. Hill, R. J.; Dabbagh, K.; Phippard, D.; Li, C.; Suttmann, R. T.; Welch, M.; Papp, E.; Song, K. W.; Chang, K. C.; Leaffer, D.; Kim, Y. N.; Roberts, R. T.; Zabka, T. S.; Aud, D.; Dal, P. J.; Manning, A. M.; Peng, S. L.; Goldstein, D. M.; Wong, B. R. Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J. Pharmacol. Exp. Ther. 2008, 527, 610-619.
21. Xing, L.; Shieh, H. S.; Selness, S. R.; Devraj, R. V.; Walker, J. K.; Devadas, B.; Hope, H. R.; Compton, R. P.; Schindler, J. F.; Hirsch, J. L.; Benson, A. G.; Kurumbail, R. G.; Stegeman, R. A.; Williams, J. M.; Broadus, R. M.; Walden, Z.; Monahan, J. B. Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804. Biochemistry 2009, 48, 6402-6411.
22. Murali Dhar, T. G.; Wrobleski, S. T.; Lin, S.; Furch, J. A.; Nirschl, D. S.; Fan, Y.; Todderud, G.; Pitt, S.; Doweyko, A. M.; Sack, J. S.; Mathur, A.; McKinnon, M.; Barrish, J. C.; Dodd, J. H.; Schieven, G. L.; Leftheris, K. Synthesis and SAR of p38alpha MAP kinase inhibitors based on heterobicyclic scaffolds. Bioorg. Med. Chem. Lett. 2007, 17, 5019-5024.
23. Wang, Z.; Canagarajah, B. J.; Boehm, J. C.; Kassisa, S.; Cobb, M. H.; Young, P. R.; abdel-Meguid, S.; Adams, J. L.; Goldsmith, E. J. Structural basis of inhibitor selectivity in MAP kinases. Structure 1998, 5, 1117-1128.
24. Fitzgerald, C. E.; Patel, S. B.; Becker, J. W.; Cameron, P. M.; Zaller, D.; Pikounis, V. B.; O'Keefe, S. J.; Scapin, G. Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity. Nat. Struct. Biol. 2003, 10, 164-169.
25. Herberich, B.; Cao, G. Q.; Chakrabarti, P. P.; Falsey, J. R.; Pettus, L.; Rzasa, R. M.; Reed, A. B.; Reichelt, A.; Sham, K.; Thaman, M.; Wurz, R. P.; Xu, S.; Zhang, D.; Hsieh, F.; Lee, M. R.; Syed, R.; Li, V.; Grosfeld, D.; Plant, M. H.; Henkle, B.; Sherman, L.; Middleton, S.; Wong, L. M.; Tasker, A. S. Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold. J. Med. Chem. 2008, 51, 6211-6219.
26. Lisnock, J.; Tebben, A.; Frantz, B.; O'Neill, E. A.; Croft, G.; O'Keefe, S. J.; Li, B.; Hacker, C.; de Laszlo, S.; Smith, A.; Libby, B.; Liverton, N.; Hermes, J.; LoGrasso, P. Molecular basis for p38 protein kinase inhibitor specificity. Biochemistry 1998, 37, 16573-16581.
27. Cohen, S. B.; Cheng, T. T.; Chindalore, V.; Damjanov, N.; BurgosVargas, R.; Delora, P.; Zimany, K.; Travers, H.; Caulfield, J. P. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthritis Rheum. 2009, 60, 335-344.
28. Alten, R. E.; Zerbini, C.; Jeka, S.; Irazoque, F.; Khatib, F.; Emery, P.; Bertasso, A.; Rabbia, M.; Caulfield, J. P. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann. Rheum. Dis. 2009, DOI: 10.1136/ ard.2008.104802.
29. Haddad, J. J. VX-745. Vertex Pharmaceuticals. Curr. Opin. Invest. Drugs 2001, 2, 1070-1076.
30. Weisman, M.; Furst, D.; Schiff, M.; Kauffman, R.; Merica, E.; Martin-Munley, S. A Double-blind, placebo-controlled, trial of VX-745, an oral p38 mitogen activated protein kinase (MAPK) inhibitor, in patients with rheumatoid arthritis (RA). Ann. Rheum. Dis. 2002, 61 (Suppl. 1), No. FRI0018.
31. Vertex Homepage, http://www.vrtx.com/ (accessed Sep 24, 2001).
32. Norman, P. Advances in anti-arthritic agents. SMI's Third Annual Conference. IDrugs 2002, 5, 530-538.
33. Ding, C. Drug evaluation: VX-702, a MAP kinase inhibitor for rheumatoid arthritis and acute coronary syndrome. Curr. Opin. Invest. Drugs 2006, 7, 1020-1025.
34. Damjanov, N.; Kauffman, R. S.; Spencer-Green, G. T. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum. 2009, 60, 1232-1241.
35. Nikas, S. N.; Drosos, A. A. SCIO-469 Scios Inc. Curr. Opin. Invest. Drugs 2004, 5, 1205-1212.
36. Amakye, D.; Tong, S.; Ward, C.; Beazley, W. Pharmacokinetics (PK) and pharmacodynamics (PD) of SCIO-469, a p38 gamma MAP kinase inhibitor. Clin. Pharmacol. Ther. 2004, 75, P54.
37. Schreiner, G. Kinase Inhibitors: The Next Generation of AntiArthritic Agents. Scios: Case Study in Their p38 Kinase Inhibitor Program. Presented at the Advances in Anti-Arthritic Agents SMI Conference, 2001.
38. Ji, R.-R. Peripheral and central mechanisms of inflammatory pain, with emphasis on MAP kinases. Curr. Drug Targets: Inflammation Allergy 2004, 5, 299-303.
39. Schindler, J. F.; Monahan, J. B.; Smith, W. G. p38 pathway kinases as anti-inflammatory drug targets. J. Dent. Res. 2007, 86, 800-811.
40. Tong, S. E.; Daniels, S. E.; Montano, T.; Chang, S.; Desjardins, P. SCIO-469, a novel p38 alpha MAPK inhibitor provides efficacy in acute post-surgical dental pain. Am. Soc. Clin. Pharmacol. Ther. 2004, 75, PI-1.
41. Navas, T. A.; Nguyen, A. N.; Hideshima, T.; Reddy, M.; Ma, J. Y.; Haghnazari, E.; Henson, M.; Stebbins, E. G.; Kerr, I.; O'Young, G.; Kapoun, A. M.; Chakravarty, S.; Mavunkel, B.; Perumattam, J.; Luedtke, G.; Dugar, S.; Medicherla, S.; Protter, A. A.; Schreiner, G. F.; Anderson, K. C.; Higgins, L. S. Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. Leukemia 2006, 20, 1017-1027.
42. Siegel, D. S.; Krishnan, A.; Lonial, S.; Chatta, G.; Alsina, M.; Jagannath, S.; Richardson, P.; Hohl, R. J.; Lust, J. A.; Bensinger, W.; Carrum, G.; Moreb, J.; Simic, A.; Barlogie, B.; Maziarz, R. T.; Anderson, K. C.; Lin, J.; Lowe, A.; Vetticaden, S.; Zhu, J. Phase II trial of SCIO-469 as monotherapy (M) or in combination with bortezomib (MB) in relapsed refractory multiple myeloma (MM). Blood 2006, 108, No.3580.
43. Genovese, M. C.; Cohen, S. B.; Wofsy, D.; Weinblatt, M. E.; Firestein, G. S.; Brahn, E.; Strand, V.; Baker, D. G.; Tong, S. E. A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of an Oral p38a MAPK Inhibitor, SCIO-469, in Patients with Active Rheumatoid Arthritis. Presented at the American College of Rheumatology Scientifc Meeting, San Francisco, CA, 2008; Abstract 715.
44. Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.; Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C.; Pav, S.; Proto, A.; Swinamer, A.; Tong, L.; Torcellini, C. Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate. J. Med. Chem. 2002, 45, 2994-3008.
45. Schreiber, S.; Feagan, B.; D'Haens, G.; Colombel, J. F.; Geboes, K.; Yurcov, M.; Isakov, V.; Golovenko, O.; Bernstein, C. N.; Ludwig, D.; Winter, T.; Meier, U.; Yong, C.; Steffgen, J. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Clin. Gastroenterol. Hepatol. 2006, 4, 325-334.
46. Norman, P. BMS-582949: crystalline form of a p38alpha inhibitor? WO2008079857. Expert. Opin. Ther. Pat. 2009, 19, 1165-1168.
47. Ji, P.; Gao, L.; Galbraith, S.; Kollia, G.; Xu, X.; Barrett, Y.; Kelsey, J.; Hawthorne, D.; Weiner, R.; Wang, J.; Luroe, S.; McKinnon, M.; Schieven, G.; Latek, R.; Thienel, U.; Kaul, S. Multiple-Dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Potent P38 Inhibitor BMS-582949 in Healthy Subjects. Presented at the American College of Rheumatology Scientific Meeting, San Francisco, CA, 2008; Poster 335.
48. Wang, J.; Kaul, S.; Campanha, H.; Pikul, D.; Leftheris, K.; Xu, X.; Schieven, G.; Latek, R.; Kollia, G.; Ji, P.; Weiner, R.; McKinnon, M.; Galbraith, S.; Thienel, U. Multiple Ascending Dose Study of a Potent p38 MAPK Inhibitor BMS-582949 in Subjects with Stable RA Receiving Concomitant Methotrexate. Presented at the American College of Rheumatology Scientifc Meeting, San Francisco, CA, 2008; Abstract 356.
49. ClinicalTrials.gov Home Page, http://clinicaltrials.gov/show/ NCT00605735 (accessed Jun 7, 2009).
50. BMS Homepage. http://ctr.bms.com/OneBmsCtd/InitTrialDetail Action.do?pnum = IM119-015 (accessed Jul 6, 2009).
51. Ligand Homepage, http://www.pharmacopeia.com/collaborations. php#Bristol (accessed Jul 6, 2009).
52. ClinicalTrials.gov Home Page, http://www.clinicaltrials.gov/ct2/ show/NCT00399906?term = BMS-582949&rank = 2 (accessed Jul 6, 2009).
53. ClinicalTrials.gov Home Page, http://www.clinicaltrials.gov/ct2/ show/NCT00570752?term = BMS-582949&rank = 4 (accessed Jul 6, 2009).
54. Remmers, A. p38 Inhibitors as New Therapies for Inflammatory Pain: ARRY-797. Presented at the Arrowhead Pain Therapeutic Summit, New Brunswick, NJ, 2008.
55. Array Homepage, http://investor.arraybiopharma.com/phoenix. zhtml?c= 123810&p = irol-newsArticle&ID= 1305781 &highlight = (accessed Jul 8, 2009).
56. Remmers, A.; Yates, J.; Daniels, S.; Martinez, C. A Novel p38a Inhibitor, ARRY-797, Provides Significant Analgesic Benefit following Third Molar Extraction. Presented at the American Pain Society's Annual Scientific Meeting, Tampa, FL, 2008.
57. Winski, S. L.; Humphries, M. J.; Yeh, T.; Gross, S. D.; Brown, S. A.; Anderson, D.; Wright, D.; Rodriguez, M.; Lee, P.; Munson, M.; Winkler, J. Activity of ARRY-614, an Inhibitor of p38 MAP Kinase and Angiogenic Targets, In Hematological Malignancies. Presented at the American Association for Cancer Research Annual Meeting, Denver, CO, 2009.
58. Winski, S. L.; Freeman, B. B.; Remmers, A. E.; Carter, L. L.; Wright, A. D.; Munson, M. C.; Humphries, M. J.; Murphy, V. A.; Klopfenstein, N. S.; Wallace, R. D.; Baer, B. R.; Kemp, J. F.; Nugent, C. A.; Lee, P. A.; Winhler, J. D. ARRY-614, an Inhibitor of p38 MAP Kinase and Angiogenic Targets, Is Active in Preclinical Models of Hematological Malignancies and Significantly Reduces ex-Vivo Cytokine Production in Normal Human Subjects. Presented at the 7th International Symposium on Targeted Anti-Cancer Therapeutics, Amsterdam, The Netherlands, 2009.
59. Monahan, J. B.; Hope, H.; Schindler, J.; Jungbluth, G.; Burnette, B.; Guzova, J.; Hirsch, J.; Saabye, M.; Compton, R.; Zhang, J.; Keith, R.; Anderson, G.; Stillwell, L.; Mbalaviele, G.; Webb, E.; Li, X.; Bonar, S.; Sommers, C.; Venkatraman, N.; Blorn, J.; Meyer, D.; Devraj, R.; Selness, S. Anti-Inflammatory Properties of a Novel N-Phenyl Pyridinone Inhibitor of p38 MAP Kinase: Preclinical to Clinical Translation. Presented at the Annual European Congress of Rheumatology, Copenhagen, Denmark, 2009; Abstract FRI0001.
60. Aston, N. M.; Bamborough, P.; Buckton, J. B.; Edwards, C. D.; Holmes, D. S.; Jones, K. L.; Patel, V. K.; Smee, P. A.; Somers, D. O.; Vitulli, G.; Walker, A. L. p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression. J. Med. Chem. 2009, 52, 6257-6269.
61. Adams, J. L.; Boehm, J. C.; Hall, R. J.; Jin, Q.; Kasparec, J.; Silva, D. J.; Taggart, J. J. Preparation of 2,4,8-Trisubstituted-8H-pyrido-[2,3-d] pyrimidin-7-ones as CSBP/RK/p38 Kinase Inhibitors. WO2002059083, 2002.
62. GlaxoSmithKline Homepage, http://www.gsk.com/investors/ product-pipeline/pp.htm (accessed Oct 29, 2009).
63. Fabian, M. A.; Biggs, W. H., III; Treiber, D. K.; Atteridge, C. E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, P. T.; Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.; Lai, A. G.; Lelias, J. M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 2005, 23, 329-336.
64. Stelmach, J. E.; Liu, L.; Patel, S. B.; Pivnichny, J. V.; Scapin, G.; Singh, S.; Hop, C. E.; Wang, Z.; Strauss, J. R.; Cameron, P. M.; Nichols, E. A.; O'Keefe, S. J.; O'Neill, E. A.; Schmatz, D. M.; Schwartz, C. D.; Thompson, C. M.; Zaller, D. M.; Doherty, J. B. Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. Bioorg. Med. Chem. Lett. 2003, 13, 277-280.