Optimization of a series of potent, selective and orally bioavailable SYK inhibitors. Issue 19 (1st October 2020)

• Record Type: Journal Article
• Authors: Grimster, Neil P.; Gingipalli, Lakshmaiah; Barlaam, Bernard; Su, Qibin; Zheng, XiaoLan; Watson, David; Wang, Haixia; Simpson, Iain; Pike, Andy; Balazs, Amber; Boiko, Scott; Ikeda, Timothy P.; Impastato, Anna C.; Jones, Natalie H.; Kawatkar, Sameer; Kemmitt, Paul; Lamont, Scott; Patel, Joe; Read, Jon; Sarkar, Ujjal; Sha, Li; Tomlinson, Ronald C.; Wang, Haiyun; Wilson, David M.; Zehnder, Troy E.; Wang, Lianghe; Wang, Peng; Goldberg, Frederick W.; Shao, Wenlin; Fawell, Stephen; Dry, Hannah; Dowling, James E.; Edmondson, Scott D.;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 19(2020)
• Publication Date: 2020-10-01
• Subjects: SYK -- Bioavailable -- Small molecule; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127433
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.