Fused bi-heteroaryl substituted hydantoin compounds as TACE inhibitors

[Display omitted] We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-07, Vol.27 (14), p.3037-3042
Main Authors: Tong, Ling, Kim, Seong Heon, Rosner, Kristin, Yu, Wensheng, Shankar, Bandarpalle B., Chen, Lei, Li, Dansu, Dai, Chaoyang, Girijavallabhan, Vinay, Popovici-Muller, Janeta, Yang, Liping, Zhou, Guowei, Kosinski, Aneta, Siddiqui, M. Arshad, Shih, Neng-Yang, Guo, Zhuyan, Orth, Peter, Chen, Shiying, Lundell, Daniel, Niu, Xiaoda, Umland, Shelby, Kozlowski, Joseph A.
Format: Article
Language:English
Subjects:
ADAM17 Protein - antagonists & inhibitors
ADAM17 Protein - metabolism
Animals
Area Under Curve
Dogs
Enzyme Activation - drug effects
Half-Life
Haplorhini
Humans
Hydantoin
Hydantoins - chemical synthesis
Hydantoins - chemistry
Hydantoins - pharmacology
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Rats
ROC Curve
Structure-Activity Relationship
TACE inhibitors
Tumor necrosis factor-alpha
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Summary:[Display omitted] We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.05.062