Novel potent and selective pyrazolylpyrimidine-based SYK inhibitors

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127523. doi: 10.1016/j.bmcl.2020.127523.

Bernard Barlaam ¹, Scott Boiko ², Scott Boyd ³, Hannah Dry ², Lakshmaiah Gingipalli ², Timothy Ikeda ², Tony Johnson ³, Sameer Kawatkar ², Olivier Lorthioir ³, Andy Pike ³, Hannah Pollard ⁴, Jon Read ⁴, Qibin Su ², Haiyun Wang ², Huimin Wang ⁵, Lianghe Wang ⁵, Peng Wang ⁵, Scott D Edmondson ²

Affiliations

1 R&D Oncology, AstraZeneca, Cambridge, United Kingdom. Electronic address: Bernard.barlaam2@astrazeneca.com.
2 R&D Oncology, AstraZeneca, Boston, MA, United States.
3 R&D Oncology, AstraZeneca, Cambridge, United Kingdom.
4 Discovery Sciences, AstraZeneca, Cambridge, United Kingdom.
5 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, PR China.

PMID: 32877741 DOI: 10.1016/j.bmcl.2020.127523

Abstract

Hybridisation of amino-pyrimidine based Syk inhibitors (e.g. 1a) with previously reported diamine-based Syk inhibitors (e.g. TAK-659) led to the identification and optimisation of a novel pyrimidine-based series of potent and selective Syk inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group. The initial compound 5 achieved excellent Syk potency. However, it suffered from poor permeability and modest kinase selectivity. Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallography. Further optimisation of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition.

Keywords

Diamine; Kinase selectivity; SYK.

Name
Email *

	Sorry, but the email address you supplied was invalid.