Rational Design of 2‑Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors
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 compo...
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Published in | Journal of medicinal chemistry Vol. 63; no. 24; pp. 15852 - 15863 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
24.12.2020
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/acs.jmedchem.0c01573 |