title: Concise SAR Exploration Based on the "Head-to-Tail" Approach: Discovery of PI4KIIIα Inhibitors Bearing Diverse Scaffolds.
abstract: In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy. PI4KIIIα is one of four mammalian phosphatidylinositol-4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. In this letter, a novel "head-to-tail" approach to discover a diverse set of PI4KIIIα inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Satoru
authors: S
authors: Noji
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Noriyoshi
authors: N
authors: Seki
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Takaki
authors: T
authors: Maeba
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Takayuki
authors: T
authors: Sakai
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Eiichi
authors: E
authors: Watanabe
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Katsuya
authors: K
authors: Maeda
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Kyoko
authors: K
authors: Fukushima
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Toru
authors: T
authors: Noguchi
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Kazuya
authors: K
authors: Ogawa
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Yukiyo
authors: Y
authors: Toyonaga
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Tamotsu
authors: T
authors: Negoro
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Hisashi
authors: H
authors: Kawasaki
authors: Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors: Makoto
authors: M
authors: Shiozaki
keywords: HCV; PI4KIIIα; diverse scaffolds; head-to-tail approach