2. Academic Validation
  3. Identification and optimisation of a pyrimidopyridone series of IRAK4 inhibitors

Identification and optimisation of a pyrimidopyridone series of IRAK4 inhibitors

  • Bioorg Med Chem. 2022 Jun 1;63:116729. doi: 10.1016/j.bmc.2022.116729.
Iain A Cumming 1,  Sébastien L Degorce 2,  Anna Aagaard 3,  Erin L Braybrooke 2,  Nichola L Davies 2,  Coura R Diène 2,  Andrew J Eatherton 2,  Hannah R Felstead 2,  Sam D Groombridge 2,  Eva M Lenz 2,  Yunxia Li 4,  Youfeng Nai 4,  Stuart Pearson 2,  Graeme R Robb 2,  James S Scott 2,  Oliver R Steward 2,  Chengyan Wu 4,  Yafeng Xue 3,  Lanping Zhang 4,  Yanxiu Zhang 4
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge Science Park, Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom. Electronic address: iain.cumming@astrazeneca.com.
  • 2 Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge Science Park, Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom.
  • 3 Discovery Sciences, R&D, AstraZeneca, Gothenburg, SE-431 83 Mölndal, Sweden.
  • 4 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176 PR China.
PMID: 35439688 DOI: 10.1016/j.bmc.2022.116729
Abstract

In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.

Keywords

DLBCL; IRAK4; Novel hinge binder; Pyrimidopyridone.

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