2. Academic Validation
  3. Optimization of a series of potent, selective and orally bioavailable SYK inhibitors

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

Affiliations

  • 1 Oncology R&D, AstraZeneca, Waltham, USA. Electronic address: neil.grimster@astrazeneca.com.
  • 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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