Discovery of 3-morpholino-imidazole[1,5- a ]pyrazine BTK inhibitors for rheumatoid arthritis
Journal Article
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· Bioorganic and Medicinal Chemistry Letters
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8-Amino-imidazo[1,5-a]pyrazine-based Bruton’s tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- INDUSTRY
- OSTI ID:
- 1404954
- Journal Information:
- Bioorganic and Medicinal Chemistry Letters, Vol. 27, Issue 16; ISSN 0960-894X
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- ENGLISH
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