- Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity
-
IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent molecule 19 that achieves robust in vivo inhibition of cytokines relevant to human disease.
- Rajapaksa, Naomi S.,Gobbi, Alberto,Drobnick, Joy,Do, Steven,Kolesnikov, Aleksandr,Liang, Jun,Chen, Yongsheng,Sujatha-Bhaskar, Swathi,Huang, Zhiyu,Brightbill, Hans,Francis, Ross,Yu, Christine,Choo, Edna F.,Dement, Kevin,Ran, Yingqing,An, Le,Emson, Claire,Maher, Jonathan,Wai, John,McKenzie, Brent S.,Lupardus, Patrick J.,Zarrin, Ali A.,Kiefer, James R.,Bryan, Marian C.
-
p. 327 - 333
(2019/12/02)
-
- PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
-
Compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), and methods of use as lnterleukin-1 Receptor Associated Kinase (IRAK4) inhibitors are described herein.
- -
-
-
- PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
-
Compounds of Formula (0), Formula (I), and Formula (II) and methods of use as Interleukin-1 Receptor Associated Kinase (IRAK4) inhibitors are described herein.
- -
-
-
- Cyclopenta[g]quinazolinone-based inhibitors of thymidylate synthase targeting α-folate receptor overexpressing tumours: synthetic approaches to 4-{N-[(6RS)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benz
-
An advanced intermediate for the synthesis of cyclopenta[g]quinazolinone-based antifolates such as (6RS)-CB300945 was prepared by a convergent methodology. The oxo-functionality required for the formation of the C-6-N-10 bond in 4 was introduced in the in
- Bavetsias, Vassilios,Henderson, Elisa A.,McDonald, Edward
-
p. 1537 - 1543
(2007/10/03)
-
- 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
-
The Compound of Formula I and pharmaceutically acceptable salts thereof in the treatment of cyclooxygenase-2 mediated diseases are disclosed.
- -
-
-
- Cyclooxygenase-2 inhibitors. Synthesis and pharmacological activities of 5-methanesulfonamido-1-indanone derivatives
-
The recent discovery of an alternative form cyclooxygenase (cyclooxygenase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti- inflammatory drugs with fewer side effects tha
- Li,Black,Chan,Ford-Hutchinson,Gauthier,Gordon,Guay,Kargman,Lau,Mancini,Ouimet,Roy,Vickers,Wong,Young,Zamboni,Prasit
-
p. 4897 - 4905
(2007/10/03)
-
- Synthesis of 5-methanesulfonamido-6-(2,4-difluorophenylthio)-1-indanone
-
The ethylene ketal of 5-nitro-6-bromo-1-indanone 6 was prepared via oxidation of N-(6-Bromo-5-indanyl)-acetamide 1. A subsequent mild displacement and elaboration to 6-thiosubstituted-5-amino indanone derivative 10 is also described.
- Scheigetz,Zamboni,Roy
-
p. 2791 - 2806
(2007/10/02)
-
- ALKANESULFONAMIDO-1-INDANONE DERIVATIVES AS INHIBITORS OF CYCLOOXYGENASE
-
Disclosed are compounds of Formula I useful in the treatment of cyclooxygenase mediated diseases such as pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, bums, injuries
- -
-
-