School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.
Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, Hainan, China.
J Med Chem. 2020 Dec 24;63(24):15852-15863. doi: 10.1021/acs.jmedchem.0c01573. Epub 2020 Dec 8.
To validate the hypothesis that Tyr748 is a crucial residue to aid the discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified a series of 2-chloroadenine derivatives based on the hit clofarabine. Structure-based design targeting Tyr748 in PDE8 resulted in the lead compound (IC = 0.010 μM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, bound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 Å with Tyr748, which possibly interprets the 220-fold selectivity of against PDE2A. Additionally, oral administration of compound achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.
为验证 Tyr748 是帮助发现高度选择性磷酸二酯酶 8A（PDE8A）抑制剂的关键残基这一假说，我们基于先导化合物克洛拉滨，鉴定了一系列 2-氯腺嘌呤衍生物。针对 PDE8 中 Tyr748 的基于结构的设计产生了先导化合物 （IC = 0.010 μM），具有高选择性和合理的类药性特征。在 X 射线晶体结构中， 与 PDE8A 以不同于 3-异丁基-1-甲基黄嘌呤（泛 PDE 抑制剂）的模式结合，并与 Tyr748 形成 2.7 Å 的氢键，这可能解释了 对 PDE2A 的 220 倍选择性。此外，化合物 的口服给药对血管性痴呆（VaD）表现出显著的治疗效果，表明 PDE8 抑制剂可能成为潜在的抗 VaD 药物。
