Structural highlights
Function
PDE8A_HUMAN Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in maintaining basal levels of the cyclic nucleotide and/or in the cAMP regulation of germ cell development.[1]
Publication Abstract from PubMed
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 muM) 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 A 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.
Rational Design of 2-Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors.,Huang Y, Wu XN, Zhou Q, Wu Y, Zheng D, Li Z, Guo L, Luo HB J Med Chem. 2020 Dec 24;63(24):15852-15863. doi: 10.1021/acs.jmedchem.0c01573., Epub 2020 Dec 8. PMID:33291877[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang H, Yan Z, Yang S, Cai J, Robinson H, Ke H. Kinetic and Structural Studies of Phosphodiesterase-8A and Implication on the Inhibitor Selectivity. Biochemistry. 2008 Nov 5. PMID:18983167 doi:10.1021/bi801487x
- ↑ Huang Y, Wu XN, Zhou Q, Wu Y, Zheng D, Li Z, Guo L, Luo HB. Rational Design of 2-Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors. J Med Chem. 2020 Dec 24;63(24):15852-15863. PMID:33291877 doi:10.1021/acs.jmedchem.0c01573
