Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation

ACS Medicinal Chemistry Letters

Volumn 6, Issue 6, 2015, Pages 677-682

  McElroy, William T ^a   Tan, Zheng ^a   Ho, Ginny ^a   Paliwal, Sunil ^a   Li, Guoqing ^a   Seganish, W Michael ^a   Tulshian, Deen ^a   Tata, James ^a   Fischmann, Thierry O ^b   Sondey, Christopher ^c   Bian, Hong ^d   Bober, Loretta ^d   Jackson, James ^d   Garlisi, Charles G ^c   Devito, Kristine ^c   Fossetta, James ^d   Lundell, Daniel ^d   Niu, Xiaoda ^c  

^a Bristol Myers Squibb   (United States)

^b Structural Chemistry   (United States)

^c In Vitro Pharmacology ^*  (United States)

^d MERCK RESEARCH LABORATORIES   (United States)

Author keywords

drug discovery; inflammation; Interleukin 1 receptor associated kinase 4; SAR; structure based drug design

Indexed keywords

DEXAMETHASONE; ENZYME INHIBITOR; GAMMA INTERFERON; INTERLEUKIN 1 RECEPTOR ASSOCIATED KINASE 4; INTERLEUKIN 1BETA; INTERLEUKIN 6; INTERLEUKIN 8; PIPERIDINE DERIVATIVE; PYRAZOLE DERIVATIVE; SULFONE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA;

AEROBIC METABOLISM; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CYTOKINE PRODUCTION; DEMETHYLATION; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG CONFORMATION; DRUG IDENTIFICATION; DRUG METABOLISM; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME INHIBITION; EXPERIMENTAL ARTHRITIS; FEMALE; HYDROGEN BOND; IC50; INFLAMMATION; LIMIT OF DETECTION; LIPOPHILICITY; LIVER CELL; METABOLIC STABILITY; MOUSE; NONHUMAN; OXIDATION; PH; PRIORITY JOURNAL; RAT; X RAY CRYSTALLOGRAPHY;

RODENTIA;

EID: 84935898583     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/acsmedchemlett.5b00106     Document Type: Article

References (23)

1. Pawelec, G.; Goldeck, D.; Derhovanessian, E. Inflammation, ageing and chronic disease Curr. Opin. Immunol. 2014, 29, 23 - 28
2. Jacobson, D. L.; Gange, S. J.; Rose, N. R.; Graham, N. M. H. Epidemiology and estimated population burden of selected autoimmune diseases in the United States Clin. Immunol. Immunopathol. 1997, 84, 223 - 243
3. Trinchieri, G. Cancer and Inflammation: An old intuition with rapidly evolving new concepts Annu. Rev. Immunol. 2012, 30, 677 - 706
4. Libby, P. Inflammation and cardiovascular disease mechanisms Am. J. Clin. Nutr. 2006, 83, 456s - 460s
5. Choy, E. H.; Kavanaugh, A. F.; Jones, S. A. The problem of choice: current biologic agents and future prospects in RA Nat. Rev. Rheumatol. 2013, 9, 154 - 163
6. Ghoreschi, K.; Gadina, M. Jakpot! New small molecules in autoimmune and inflammatory diseases Exp. Dermatol. 2014, 23, 7 - 11
7. Wang, X. H.; Smith, C.; Yin, H. Targeting Toll-like receptors with small molecule agents Chem. Soc. Rev. 2013, 42, 4859 - 4866
8. Li, S. Y.; Strelow, A.; Fontana, E. J.; Wesche, H. IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase Proc. Natl. Acad. Sci. USA 2002, 99, 5567 - 5572
9. O'Neill, L. A. J. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress Immunol. Rev. 2008, 226, 10 - 18
10. Suzuki, N.; Saito, T. IRAK-4-a shared NF-kappa B activator in innate and acquired immunity Trends Immunol. 2006, 27, 566 - 572
11. Picard, C.; Puel, A.; Bonnet, M.; Ku, C. L.; Bustamante, J.; Yang, K.; Soudais, C.; Dupuis, S.; Feinberg, J.; Fieschi, C.; Elbim, C.; Hitchcock, R.; Lammas, D.; Davies, G.; Al-Ghonaium, A.; Al-Rayes, H.; Al-Jumaah, S.; Al-Hajjar, S.; Al-Mohsen, I. Z.; Frayha, H. H.; Rucker, R.; Hawn, T. R.; Aderem, A.; Tufenkeji, H.; Haraguchi, S.; Day, N. K.; Good, R. A.; Gougerot-Pocidalo, M. A.; Ozinsky, A.; Casanova, J. L. Pyogenic bacterial infections in humans with IRAK-4 deficiency Science 2003, 299, 2076 - 2079
12. Dou, H.; Song, Y.; Liu, X.; Yang, L.; Jiang, N.; Chen, D.; Li, E.; Tan, R.; Hou, Y. A novel benzenediamine derivate rescued mice from experimental sepsis by attenuating proinflammatory mediators via IRAK4 Am. J. Respir. Cell Mol. 2014, 51, 191 - 200
13. Tumey, L. N.; Boschelli, D. H.; Bhagirath, N.; Shim, J.; Murphy, E. A.; Goodwin, D.; Bennett, E. M.; Wang, M. M.; Lin, L. L.; Press, B.; Shen, M.; Frisbie, R. K.; Morgan, P.; Mohan, S.; Shin, J.; Rao, V. R. Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4 Bioorg. Med. Chem. Lett. 2014, 24, 2066 - 2072
14. Chaudhary, D.; Robinson, S.; Romero, D. L. Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders J. Med. Chem. 2015, 58, 96 - 110
15. Hynes, J.; Nair, S. K. Advances in the discovery of small-molecule IRAK4 inhibitors Annu. Rep. Med. Chem. 2014, 49, 117 - 133
16. Toledo, L. M.; Lydon, N. B.; Elbaum, D. The structure-based design of ATP-site directed protein kinase inhibitors Curr. Med. Chem. 1999, 6, 775 - 805
17. See Supporting Information for complete description of compound synthesis.
18. Reddy, G. J.; Latha, D.; Rao, K. S. A clean and rapid synthesis of 5-amino and 5-alkoxycarbonylpyrazoles using montmorillonite under acid free conditions Org. Prep. Proced. Int. 2004, 36, 494 - 498
19. Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.; Hsieh, Y. S.; Wainhaus, S.; Broske, L.; Prelusky, D.; Nomeir, A.; White, R. E. Cassette-accelerated rapid rat screen: a systematic procedure for the dosing and liquid chromatography/atmospheric pressure ionization tandem mass spectrometric analysis of new chemical entities as part of new drug discovery Rapid Commun. Mass Spectrom. 2001, 15, 335 - 340
20. Ritchie, T. J.; Macdonald, S. J. F. The impact of aromatic ring count on compound developability-are too many aromatic rings a liability in drug design? Drug Discovery Today 2009, 14, 1011 - 1020
21. Palsson-McDermott, E. M.; O'Neill, L. A. J. The potential of targeting Toll-like receptor 2 in autoimmune and inflammatory diseases Irish J. Med. Sci. 2007, 176, 253 - 260
22. He, H.; Lyons, K. A.; Shen, X.; Yao, Z.; Bleasby, K.; Chan, G.; Hafey, M.; Salituro, G. M.; Cohen, L. H.; Tang, W. Utility of unbound plasma drug levels and P-glycoprotein transport data in prediction of central nervous system exposure Xenobiotica 2009, 39, 687 - 693
23. Asquith, D. L.; Miller, A. M.; McInnes, I. B.; Liew, F. Y. Animal models of rheumatoid arthritis Eur. J. Immunol. 2009, 39, 2040 - 2044