Bioorganic and medicinal chemistry letters (2020)
Update date:2022-08-16
Topics:
Balazs, Amber
Barlaam, Bernard
Boiko, Scott
Dowling, James E.
Dry, Hannah
Edmondson, Scott D.
Fawell, Stephen
Gingipalli, Lakshmaiah
Goldberg, Frederick W.
Grimster, Neil P.
Ikeda, Timothy P.
Impastato, Anna C.
Jones, Natalie H.
Kawatkar, Sameer
Kemmitt, Paul
Lamont, Scott
Patel, Joe
Pike, Andy
Read, Jon
Sarkar, Ujjal
Sha, Li
Shao, Wenlin
Simpson, Iain
Su, Qibin
Tomlinson, Ronald C.
Wang, Haixia
Wang, Haiyun
Wang, Lianghe
Wang, Peng
Watson, David
Wilson, David M.
Zehnder, Troy E.
Zheng, XiaoLan
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.
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