Rational Design of 2‑Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors

• Published in: Journal of medicinal chemistry Vol. 63; no. 24; pp. 15852 - 15863
• Main Authors: Huang, Yadan, Wu, Xu-Nian, Zhou, Qian, Wu, Yinuo, Zheng, Dongxiao, Li, Zhe, Guo, Lei, Luo, Hai-Bin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.12.2020; Amer Chemical Soc
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Adenine - analogs & derivatives; Adenine - chemistry; Adenine - metabolism; Adenine - pharmacology; Adenine - therapeutic use; Administration, Oral; Animals; Behavior, Animal - drug effects; Binding Sites; Chemistry, Medicinal; Crystallography, X-Ray; Dementia, Vascular - drug therapy; Dementia, Vascular - pathology; Disease Models, Animal; Drug Design; Half-Life; Humans; Inhibitory Concentration 50; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Life Sciences & Biomedicine; Mice; Molecular Dynamics Simulation; Pharmacology & Pharmacy; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - metabolism; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - therapeutic use; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; DEMENTIA; ASSAY; MEMORY DEFICITS; PERFORMANCE; CAFFEINE; OPTIMIZATION; DISCOVERY; PDE INHIBITORS; ROLIPRAM
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01573

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 3a (IC50 = 0.010 μM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, 3a 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 3a against PDE2A. Additionally, oral administration of compound 3a achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.