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Publication Abstract from PubMed

We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.

A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors.,Bolduc PN, Pfaffenbach M, Evans R, Xin Z, Henry KL, Gao F, Fang T, Silbereis J, Vera Rebollar J, Li P, Chodaparambil JV, Metrick C, Peterson EA ACS Med Chem Lett. 2024 Apr 26;15(5):714-721. doi: , 10.1021/acsmedchemlett.4c00102. eCollection 2024 May 9. PMID:38746903^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.