title: Discovery of novel 5-hydroxy-4-pyridone-3-carboxy acids as potent inhibitors of influenza Cap-dependent endonuclease.
abstract: 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.
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan. Electronic address: masayoshi.miyagawa@shionogi.co.jp.
authors: Masayoshi
authors: M
authors: Miyagawa
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Toshiyuki
authors: T
authors: Akiyama
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Minako
authors: M
authors: Mikamiyama-Iwata
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Kazunari
authors: K
authors: Hattori
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Naoko
authors: N
authors: Kurihara
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Yoshiyuki
authors: Y
authors: Taoda
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Chika
authors: C
authors: Takahashi-Kageyama
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Noriyuki
authors: N
authors: Kurose
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Hidenori
authors: H
authors: Mikamiyama
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Naoyuki
authors: N
authors: Suzuki
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Kenji
authors: K
authors: Takaya
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Kenji
authors: K
authors: Tomita
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Kenji
authors: K
authors: Matsuo
authors: Research Laboratory for Development, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Kenji
authors: K
authors: Morimoto
authors: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Ryu
authors: R
authors: Yoshida
authors: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Takao
authors: T
authors: Shishido
authors: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Tomokazu
authors: T
authors: Yoshinaga
authors: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Akihiko
authors: A
authors: Sato
authors: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
authors: Makoto
authors: M
authors: Kawai
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004720:Endonucleases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009975:Orthomyxoviridae / Q000187:drug effects*; D011728:Pyridones / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D011728:Pyridones; C534143:4-pyridone; D004720:Endonucleases
keywords: Anti-influenza drug; Cap-dependent endonuclease; Chelator; Pyridone; Virtual modeling