{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["15(5)"],"submitter":["Bolduc PN"],"pubmed_abstract":["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."],"journal":["ACS medicinal chemistry letters"],"pagination":["714-721"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11089553"],"repository":["biostudies-literature"],"pubmed_title":["A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors."],"pmcid":["PMC11089553"],"pubmed_authors":["Bolduc PN","Metrick C","Pfaffenbach M","Li P","Peterson EA","Chodaparambil JV","Gao F","Vera Rebollar J","Evans R","Henry KL","Fang T","Silbereis J","Xin Z"],"additional_accession":[]},"is_claimable":false,"name":"A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 May","modification":"2026-06-02T17:59:56.478Z","creation":"2026-04-18T03:12:27.785Z"},"accession":"S-EPMC11089553","cross_references":{"pubmed":["38746903"],"doi":["10.1021/acsmedchemlett.4c00102"]}}