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Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2018-05-04 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01862
Joseph T Madak , Christine R Cuthbertson , Yoshinari Miyata , Shuzo Tamura , Elyse M Petrunak 1 , Jeanne A Stuckey 1 , Yanyan Han , Miao He , Duxin Sun , Hollis D Showalter , Nouri Neamati
Affiliation  

We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC50 = 9.71 ± 1.4 nM) and 43 (DHODH IC50 = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC50 = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability (F = 56%) and an elimination t1/2 = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.

中文翻译:

4-喹啉羧酸作为二氢乳清酸脱氢酶抑制剂的设计、合成和生物学评价

我们追求一种结构导向的方法来开发改进的二氢乳清酸脱氢酶 (DHODH) 抑制剂,目标是在 DHODH 和 brequinar 类抑制剂之间形成新的相互作用。在 brequinar 结合口袋中鉴定了两个潜在的残基,T63 和 Y356,适用于新的 H 键相互作用。类似物旨在维持基本的药效团并通过战略性定位的氢键接受基团形成新的静电相互作用。这一努力导致发现了有效的基于喹啉的类似物41 (DHODH IC 50 = 9.71 ± 1.4 nM) 和43 (DHODH IC 50 = 26.2 ± 1.8 nM)。43之间的共晶结构DHODH 描述了一种新的水介导的与 T63 的氢键相互作用。额外的优化导致 1,7-萘啶46 (DHODH IC 50 = 28.3 ± 3.3 nM) 与 Y356 形成新的氢键。重要的是,化合物41具有显着的口服生物利用度 ( F = 56%) 和消除t 1/2 = 2.78 h (PO 给药)。总之,这些数据支持对我们的先导化合物进行进一步的临床前研究,以选择早期临床开发的候选药物。
更新日期:2018-05-04
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