2. Academic Validation
  3. Discovery of Potent and Efficacious Influenza PB2 Inhibitors

Discovery of Potent and Efficacious Influenza PB2 Inhibitors

  • ACS Med Chem Lett. 2025 Dec 12;17(1):249-256. doi: 10.1021/acsmedchemlett.5c00674.
Jun Wu 1,  Yongfu Liu 1,  Dongbo Li 1,  Lisha Wang 2,  Werner Neidhart 3,  Bo Chen 1,  Remo Hochstrasser 4,  Andreas Kuglstatter 4,  Rodolfo Gasser 5,  Hongxia Qiu 6,  Tianlai Shi 4,  Suzan Keen Chao 7,  Junjun Gao 7,  Hong C Shen 1,  Xuefei Tan 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry, China Innovation Center of Roche, Shanghai 201203, China.
  • 2 CADD, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • 3 Medicinal Chemistry, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • 4 Lead Discovery, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • 5 Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • 6 Pharmaceutical Sciences, China Innovation Center of Roche, Shanghai 201203, China.
  • 7 Virology Discovery, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
PMID: 41531980 DOI: 10.1021/acsmedchemlett.5c00674
Abstract

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.

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