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 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.