Optimization of a series of potent, selective and orally bioavailable SYK inhibitors
| Autor: | Neil P. Grimster, Lakshmaiah Gingipalli, Bernard Barlaam, Qibin Su, XiaoLan Zheng, David Watson, Haixia Wang, Iain Simpson, Andy Pike, Amber Balazs, Scott Boiko, Timothy P. Ikeda, Anna C. Impastato, Natalie H. Jones, Sameer Kawatkar, Paul Kemmitt, Scott Lamont, Joe Patel, Jon Read, Ujjal Sarkar, Li Sha, Ronald C. Tomlinson, Haiyun Wang, David M. Wilson, Troy E. Zehnder, Lianghe Wang, Peng Wang, Frederick W. Goldberg, Wenlin Shao, Stephen Fawell, Hannah Dry, James E. Dowling, Scott D. Edmondson |
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| Rok vydání: | 2020 |
| Předmět: |
ERG1 Potassium Channel
Binding Sites Indazoles Molecular Structure Organic Chemistry Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry Mice Structure-Activity Relationship Drug Discovery Microsomes Liver Animals Humans Syk Kinase Molecular Medicine Caco-2 Cells Rats Wistar Protein Kinase Inhibitors Molecular Biology Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 30:127433 |
| ISSN: | 0960-894X |
| Popis: | Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition. As a result, we identified 30, which exhibited no hERG activity but unfortunately was poorly absorbed in rats and mice. We also identified a SYK chemical probe, 17, which exhibits excellent potency at SYK, and an adequate rodent PK profile to support in vivo efficacy/PD studies. |
| Databáze: | OpenAIRE |
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