1660114-31-7Relevant articles and documents
Scaffold-Hopping Approach to Discover Potent, Selective, and Efficacious Inhibitors of NF-?°B Inducing Kinase
Blaquiere, Nicole,Castanedo, Georgette M.,Burch, Jason D.,Berezhkovskiy, Leonid M.,Brightbill, Hans,Brown, Suzanne,Chan, Connie,Chiang, Po-Chang,Crawford, James J.,Dong, Teresa,Fan, Peter,Feng, Jianwen,Ghilardi, Nico,Godemann, Robert,Gogol, Emily,Grabbe, Alice,Hole, Alison J.,Hu, Baihua,Hymowitz, Sarah G.,Ismaili, Moulay Hicham Alaoui,Le, Hoa,Lee, Patrick,Lee, Wyne,Lin, Xingyu,Liu, Ning,McEwan, Paul A.,McKenzie, Brent,Silvestre, Hernani L.,Suto, Eric,Sujatha-Bhaskar, Swathi,Wu, Guosheng,Wu, Lawren C.,Zhang, Yamin,Zhong, Zoe,Staben, Steven T.
, p. 6801 - 6813 (2018/07/05)
NF-?°B-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-?°B pathway downstream from multiple TNF receptor family members, including BAFF, which has been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report herein the discovery of lead chemical series of NIK inhibitors that were identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compounds were modified to address glutathione conjugation and amide hydrolysis. These highly potent compounds exhibited selective inhibition of LTβR-dependent p52 translocation and transcription of NF-?°B2 related genes. Compound 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo.
ALKYNYL ALCOHOLS AND METHODS OF USE
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Page/Page column 96; 116; 204, (2015/03/13)
The invention relates to compounds of Formula (0): wherein A1-A8, R4 and R5 each has the meaning as described herein. Compounds of Formula (0) and pharmaceutical compositions thereof are useful in the treatment of diseases and disorders in which undesired or over-activation of NF-kB signaling is observed.
