1. Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.
- Author
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Grimster NP, Gingipalli L, Balazs A, Barlaam B, Boiko S, Boyd S, Dry H, Goldberg FW, Ikeda T, Johnson T, Kawatkar S, Kemmitt P, Lamont S, Lorthioir O, Mfuh A, Patel J, Pike A, Read J, Romero R, Sarkar U, Sha L, Simpson I, Song K, Su Q, Wang H, Watson D, Wu A, Zehnder TE, Zheng X, Li S, Dong Z, Yang D, Song Y, Wang P, Liu X, Dowling JE, and Edmondson SD
- Subjects
- Syk Kinase, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases, Signal Transduction
- Abstract
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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