- Discovery of 5-phenoxy-2-aminopyridine derivatives as potent and selective irreversible inhibitors of bruton’s tyrosine kinase
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As a member of the tyrosine protein kinase Tec (TEC) family, Bruton’s tyrosine kinase (BTK) is considered a promising therapeutic target due to its crucial roles in the B cell receptor (BCR) signaling pathway. Although many types of BTK inhibitors have been reported, there is an unmet need to achieve selective BTK inhibitors to reduce side effects. To obtain BTK selectivity and efficacy, we designed a novel series of type II BTK inhibitors which can occupy the allosteric pocket induced by the DFG-out conformation and introduced an electrophilic warhead for targeting Cys481. In this article, we have described the structure-activity relationships (SARs) leading to a novel series of potent and selective piperazine and tetrahydroisoquinoline linked 5-phenoxy-2-aminopyridine irreversible inhibitors of BTK. Compound 18g showed good potency and selectivity, and its biological activity was evaluated in hematological tumor cell lines. The in vivo efficacy of 18g was also tested in a Raji xenograft mouse model, and it significantly reduced tumor size, with 46.8% inhibition compared with vehicle. Therefore, we have presented the novel, potent, and selective irreversible inhibitor 18g as a type II BTK inhibitor.
- Cho, Hyewon,Choi, Byeong Jo,Ha, Ju Hyun,Jeon, Raok,Jeong, Ji Hye,Kang, Jong Soon,Lee, Da Kyung,Lee, Eun,Ryu, Jae-Ha
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- Discovery of novel FMS kinase inhibitors as anti-inflammatory agents
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The optimization of the arylamide lead 2 resulted in identification of a highly potent series of 2,4-disubstituted arylamides. Compound 8 (FMS kinase IC50 = 0.0008 μM) served as a proof-of-concept candidate in a collagen-induced model of arthri
- Illig, Carl R.,Chen, Jinsheng,Wall, Mark J.,Wilson, Kenneth J.,Ballentine, Shelley K.,Rudolph, M. Jonathan,DesJarlais, Renee L.,Chen, Yanmin,Schubert, Carsten,Petrounia, Ioanna,Crysler, Carl S.,Molloy, Christopher J.,Chaikin, Margery A.,Manthey, Carl L.,Player, Mark R.,Tomczuk, Bruce E.,Meegalla, Sanath K.
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p. 1642 - 1648
(2008/12/22)
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- AROMATIC AMIDES AS INHIBITORS OF C-FMS KINASE
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The invention relates to compounds of Formula (I), wherein A, X, R2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula (I), are also provided.
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Page/Page column 115-116
(2008/06/13)
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