Drug Design and Discovery Center, University of Namur, Namur, Belgium.
J Med Chem. 2011 Aug 11;54(15):5320-34. doi: 10.1021/jm2006782. Epub 2011 Jul 18.
Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.
色氨酸 2,3-双加氧酶（TDO）介导的色氨酸分解代谢是外周免疫耐受的重要机制，有助于肿瘤免疫抵抗。因此，IDO 抑制是药物开发研究的一个活跃领域。最近，我们的研究小组表明，色氨酸 2,3-双加氧酶（TDO），一种不相关的肝酶，也催化色氨酸降解的第一步，也在许多肿瘤中表达，这种表达通过局部耗尽色氨酸来防止肿瘤排斥。在此，我们报告了一系列 3-(2-(吡啶基)乙烯基)吲哚的结构活性研究。合成了 70 多种新型衍生物，并对其 TDO 抑制活性进行了评价。对构效关系（SARs）的合理化揭示了达到高 TDO 抑制所必需的特征，特别是主要涉及 His(55)和 Thr(254)残基的密集氢键网络。我们的研究确定了一种非常有前途的化合物（58），具有良好的 TDO 抑制作用（K(i) = 5.5 μM）、高选择性和良好的口服生物利用度。事实上，选择 58 进行临床前评估。
