Identification and optimisation of a pyrimidopyridone series of IRAK4 inhibitors. (1st June 2022)

• Record Type: Journal Article
• Authors: Cumming, Iain A.; Degorce, Sébastien L.; Aagaard, Anna; Braybrooke, Erin L.; Davies, Nichola L.; Diène, Coura R.; Eatherton, Andrew J.; Felstead, Hannah R.; Groombridge, Sam D.; Lenz, Eva M.; Li, Yunxia; Nai, Youfeng; Pearson, Stuart; Robb, Graeme R.; Scott, James S.; Steward, Oliver R.; Wu, Chengyan; Xue, Yafeng; Zhang, Lanping; Zhang, Yanxiu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 63(2022)
• Publication Date: 2022-06-01
• Subjects: IRAK4 -- DLBCL -- Pyrimidopyridone -- Novel hinge binder; DLBCL diffuse large B cell lymphoma -- hERG human Ether-à-go-go-Related Gene -- HLM human liver microsomes -- IRAK4 Interleukin-1 Receptor-Associated Kinase 4 -- IMHB intramolecular hydrogen bond -- LLE lipophilic ligand efficiency -- MW Molecular Weight -- MyD88 myeloid differentiation primary response 88 -- NOE nuclear Overhauser effect -- NF-κB nuclear factor kappa B -- TLR toll-like receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116729
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.