Ogoshi Yosuke, Matsui Takuya, Mitani Ikuo, Yokota Masahiro, Terashita Masakazu, Motoda Dai, Ueyama Kazuhito, Hotta Takahiro, Ito Takashi, Suma Akira, Fukui Kenji, Deai Katsuya, Yoshiuchi Hiromi, Ito Soichiro, Abe Hiroyuki
Central Pharmaceutical Research Institute, Japan Tobacco, Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
ACS Med Chem Lett. 2025 Apr 30;16(6):1124-1130. doi: 10.1021/acsmedchemlett.5c00172. eCollection 2025 Jun 12.
Lead generation is a crucial process in drug discovery, and the identification of druglike lead compounds is essential to increase the chances of success in this field. Orally available hypoxia-inducible factor prolyl hydroxylase inhibitors have been a new treatment for renal anemia in chronic kidney disease patients. In our journey to enarodustat, approved in Japan, China, and South Korea, we adopted a pharmacophore-based scaffold-hopping strategy from binding mode analysis of known inhibitors. During the search for lead compounds, cell permeability was found to be a key factor in cell activity. Therefore, membrane permeability, ligand efficiency, and lipophilic ligand efficiency were utilized as compasses for the lead generation. We successfully identified compound bearing a [1,2,4]-triazolo-[4,3-]-pyridine core as a lead compound. Structures of enarodustat and compound differed only by the presence or absence of a phenethyl group, implying that the identification of a high-quality lead compound led to our success.
潜在客户生成是药物发现中的一个关键过程，鉴定类药物先导化合物对于提高该领域的成功几率至关重要。口服可用的缺氧诱导因子脯氨酰羟化酶抑制剂已成为慢性肾病患者肾性贫血的一种新疗法。在我们研发已在日本、中国和韩国获批的依那度司他的过程中，我们从已知抑制剂的结合模式分析出发，采用了基于药效团的骨架跃迁策略。在寻找先导化合物的过程中，发现细胞通透性是细胞活性的一个关键因素。因此，膜通透性、配体效率和亲脂性配体效率被用作潜在客户生成的导向。我们成功鉴定出带有[1,2,4]-三唑并-[4,3-]-吡啶核心的化合物作为先导化合物。依那度司他和该化合物的结构仅因苯乙基的有无而不同，这意味着鉴定出高质量的先导化合物促成了我们的成功。
