tetano
Editor, Senior Moderator
ACS Med Chem Lett
. 2025 Dec 12;17(1):249-256.
doi: 10.1021/acsmedchemlett.5c00674. eCollection 2026 Jan 8.
Discovery of Potent and Efficacious Influenza PB2 Inhibitors
Jun Wu[SUP] 1 [/SUP], Yongfu Liu[SUP] 1 [/SUP], Dongbo Li[SUP] 1 [/SUP], Lisha Wang[SUP] 2 [/SUP], Werner Neidhart[SUP] 3 [/SUP], Bo Chen[SUP] 1 [/SUP], Remo Hochstrasser[SUP] 4 [/SUP], Andreas Kuglstatter[SUP] 4 [/SUP], Rodolfo Gasser[SUP] 5 [/SUP], Hongxia Qiu[SUP] 6 [/SUP], Tianlai Shi[SUP] 4 [/SUP], Suzan Keen Chao[SUP] 7 [/SUP], Junjun Gao[SUP] 7 [/SUP], Hong C Shen[SUP] 1 [/SUP], Xuefei Tan[SUP] 1 [/SUP]
Affiliations
In pursuit of potent, efficacious influenza inhibitors with novel mechanisms, we replaced the 7-azaindole core of the PB2 inhibitor pimodivir (VX-787/JNJ872) with a 7-fluoro-substituted indazole to mitigate CYP3A- and aldehyde oxidase-mediated metabolism by lowering lipophilicity and blocking the metabolic soft spot. We further introduced a cyclopropyl-fused ring onto the bridged bicyclo[2.2.2]-octane to retain potency while reducing glucuronidation. This design converged in compound 3, where the indazole scaffold and fused cyclopropyl ring acted synergistically to improve the potency and pharmacokinetic properties. In a lethal influenza mouse challenge model, compound 3 achieved approximately a 7-fold reduction in the effective dose compared with pimodivir. It also showed significantly improved activity against selected influenza A strains versus pimodivir, highlighting its potential as a differentiated PB2 inhibitor.
Keywords: PB2 inhibitor; azaindazole; cyclopropanation; influenza.
. 2025 Dec 12;17(1):249-256.
doi: 10.1021/acsmedchemlett.5c00674. eCollection 2026 Jan 8.
Discovery of Potent and Efficacious Influenza PB2 Inhibitors
Jun Wu[SUP] 1 [/SUP], Yongfu Liu[SUP] 1 [/SUP], Dongbo Li[SUP] 1 [/SUP], Lisha Wang[SUP] 2 [/SUP], Werner Neidhart[SUP] 3 [/SUP], Bo Chen[SUP] 1 [/SUP], Remo Hochstrasser[SUP] 4 [/SUP], Andreas Kuglstatter[SUP] 4 [/SUP], Rodolfo Gasser[SUP] 5 [/SUP], Hongxia Qiu[SUP] 6 [/SUP], Tianlai Shi[SUP] 4 [/SUP], Suzan Keen Chao[SUP] 7 [/SUP], Junjun Gao[SUP] 7 [/SUP], Hong C Shen[SUP] 1 [/SUP], Xuefei Tan[SUP] 1 [/SUP]
Affiliations
- PMID: 41531980
- PMCID: PMC12794059 (available on 2027-01-08)
- DOI: 10.1021/acsmedchemlett.5c00674
In pursuit of potent, efficacious influenza inhibitors with novel mechanisms, we replaced the 7-azaindole core of the PB2 inhibitor pimodivir (VX-787/JNJ872) with a 7-fluoro-substituted indazole to mitigate CYP3A- and aldehyde oxidase-mediated metabolism by lowering lipophilicity and blocking the metabolic soft spot. We further introduced a cyclopropyl-fused ring onto the bridged bicyclo[2.2.2]-octane to retain potency while reducing glucuronidation. This design converged in compound 3, where the indazole scaffold and fused cyclopropyl ring acted synergistically to improve the potency and pharmacokinetic properties. In a lethal influenza mouse challenge model, compound 3 achieved approximately a 7-fold reduction in the effective dose compared with pimodivir. It also showed significantly improved activity against selected influenza A strains versus pimodivir, highlighting its potential as a differentiated PB2 inhibitor.
Keywords: PB2 inhibitor; azaindazole; cyclopropanation; influenza.