Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India; Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, 576 104, Karnataka, India.
Eur J Med Chem. 2019 Jul 15;174:198-215. doi: 10.1016/j.ejmech.2019.04.020. Epub 2019 Apr 16.
A new class of PDE4 inhibitors were designed and synthesized via the InCl mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed CH activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC = 0.39 ± 0.13 μM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively) showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) in Zebrafish.
我们通过 InCl 介导的吲哚杂芳基化及其钯(II)催化的 CH 活化策略，设计并合成了一类新型的 PDE4 抑制剂。通过这种方法，我们发现了一系列基于 2-(1H-吲哚-3-基)-喹喔啉的抑制剂，对 PDE4B 具有选择性，对 PDE4D 和 PDE4C 的选择性超过 27 倍和>250 倍。其中一种化合物，即 3b（PDE4B IC=0.39±0.13μM，对 PDE4D 和 C 的选择性分别约为 27 倍和>250 倍），在多发性硬化症的斑马鱼实验性自身免疫性脑脊髓炎（EAE）模型中，当以 3、10 和 30mg/kg 的剂量腹腔内给药时，显示出疗效。事实上，它阻止了所有测试剂量下疾病的进展。在 30mg/kg 的腹腔内剂量下，该化合物 3b 在佐剂诱导的关节炎大鼠中显示出良好的疗效。该化合物可显著减少关节炎大鼠的足爪体积、炎症和血管翳形成（膝关节）以及促炎基因表达/mRNA 水平。此外，该化合物在体外对 PDE4 具有选择性，且在斑马鱼中测试其可能的毒性（例如致畸性、肝毒性和心脏毒性）时是安全的。
