De Novo Design of 2-Amino-4-AlkylaminoquinazoIine-7-Carboxamides as Potential Scaffold for JAK1-Selective Inhibitors

摘要

Janus kinase 1 (JAK1) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family kinases (JAK1, JAK2, JAK3, and Tyk2), which play key roles in transmitting proliferative and inflammatory signals through the JAK-STAT (signal transducer and activator of transcription) pathway. Consequently, a large compound screening campaign was conducted, and multiple chemical entities have been tested for their therapeutic potential against various indications including myeloproliferative diseases and inflammatory diseases. In particular, due to the dominant role in signal transduction through γ_c-containing cytokine receptors, JAK1 has become an attractive target for the treatment of immunologic disorders such as rheumatoid arthritis (RA). Several lines of evidence also supports that an ideal RA therapy would minimize inhibition of JAK2 due to a proven link between JAK2 deficiency and anemia. Thus, in order to serve as an ideal therapeutic agent to target RA, a JAK1 inhibitor needs to achieve selective inhibition of JAK1 over other JAK isozymes. Recently, several chemical entities have been identified with potent JAK1 inhibitory activities, but with relatively low (6.4-20 fold) selectivity over JAK2.