Discovery of novel 5-hydroxy-4-pyridone-3-carboxy acids as potent inhibitors of influenza Cap-dependent endonuclease

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 19; pp. 4739 - 4742
• Main Authors: Miyagawa, Masayoshi, Akiyama, Toshiyuki, Mikamiyama-Iwata, Minako, Hattori, Kazunari, Kurihara, Naoko, Taoda, Yoshiyuki, Takahashi-Kageyama, Chika, Kurose, Noriyuki, Mikamiyama, Hidenori, Suzuki, Naoyuki, Takaya, Kenji, Tomita, Kenji, Matsuo, Kenji, Morimoto, Kenji, Yoshida, Ryu, Shishido, Takao, Yoshinaga, Tomokazu, Sato, Akihiko, Kawai, Makoto
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.10.2016; Elsevier
• Subjects: Anti-influenza drug; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cap-dependent endonuclease; Carboxylic Acids - chemistry; Chelator; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Drug Discovery; Endonucleases - antagonists & inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Inhibitory Concentration 50; Life Sciences & Biomedicine; Molecular Docking Simulation; Orthomyxoviridae - drug effects; Pharmacology & Pharmacy; Physical Sciences; Pyridone; Pyridones - chemistry; Science & Technology; Structure-Activity Relationship; Virtual modeling; Virtual modeling; Chelator; Anti-influenza drug; Pyridone; Cap-dependent endonuclease; VIRUS; POLYMERASE; DERIVATIVES; INTEGRASE INHIBITORS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.08.038

[Display omitted] We report the discovery of a novel series of influenza Cap-dependent EndoNuclease (CEN) inhibitors based on the 4-pyridone-carboxylic acid (PYXA) scaffold, which were found from our chelate library. Our SAR research revealed the lipophilic domain to be the key to CEN inhibition. In particular, the position between the chelate and the lipophilic domain in the derivatives was essential for enhancing the potency. Our study, based on virtual modeling, led to the identification of 2y as a potent CEN inhibitor with an IC50 of 5.12nM.