Department of Medicinal Chemistry, iMED Infection, AstraZeneca , Bellary Road, Hebbal, Bangalore 560024, India.
J Med Chem. 2014 Jul 10;57(13):5728-37. doi: 10.1021/jm500571f. Epub 2014 Jun 20.
In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.
在之前的报告中，我们描述了 1,4-氮杂吲哚的发现，这是一个通过非共价抑制脱磷酸化核糖基-2'-差向异构酶（DprE1）具有优异的体外和体内抗分枝杆菌活性的化学系列。然而，高小鼠代谢周转率和磷酸二酯酶 6（PDE6）脱靶活性限制了其发展。在此，我们报告了该系列的先导化合物优化，最终得到了强效、代谢稳定的化合物，具有稳健的药代动力学特征，没有任何 PDE6 风险。此外，我们在大鼠慢性结核病感染模型中证明了 1,4-氮杂吲哚的疗效。我们相信，1,4-氮杂吲哚系列的化合物适合进行体内组合和安全性研究。
