Optimization of a series of potent, selective and orally bioavailable SYK inhibitors

  • Bioorg Med Chem Lett. 2020 Oct 1;30(19):127433. doi: 10.1016/j.bmcl.2020.127433.
Neil P Grimster  1 ,  Lakshmaiah Gingipalli  2 ,  Bernard Barlaam  3 ,  Qibin Su  2 ,  XiaoLan Zheng  2 ,  David Watson  3 ,  Haixia Wang  2 ,  Iain Simpson  3 ,  Andy Pike  3 ,  Amber Balazs  2 ,  Scott Boiko  2 ,  Timothy P Ikeda  4 ,  Anna C Impastato  4 ,  Natalie H Jones  4 ,  Sameer Kawatkar  2 ,  Paul Kemmitt  3 ,  Scott Lamont  3 ,  Joe Patel  4 ,  Jon Read  5 ,  Ujjal Sarkar  2 ,  Li Sha  2 ,  Ronald C Tomlinson  4 ,  Haiyun Wang  2 ,  David M Wilson  3 ,  Troy E Zehnder  2 ,  Lianghe Wang  6 ,  Peng Wang  6 ,  Frederick W Goldberg  3 ,  Wenlin Shao  2 ,  Stephen Fawell  2 ,  Hannah Dry  2 ,  James E Dowling  2 ,  Scott D Edmondson  2
Affiliations
  • 1. Oncology R&D, AstraZeneca, Waltham, USA. Electronic address: [email protected].
  • 2. Oncology R&D, AstraZeneca, Waltham, USA.
  • 3. Oncology R&D, AstraZeneca, Cambridge, UK.
  • 4. Discovery Sciences, R&D, AstraZeneca, Waltham, USA.
  • 5. Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 6. Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, PR China.
PMID: 32717371 DOI: 10.1016/j.bmcl.2020.127433
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.

Keywords
Bioavailable; SYK; Small molecule.
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