Synthesis and Pharmacological Evaluation of 6,7-Dihydro‑3H‑Oxazolo[3,4‑a]Pyrazine-5,8-Dione Compounds as Inhibitors of Phosphodiesterases 4 and 5

TL;DR

Researchers developed a new compound that inhibits two enzymes linked to prostate issues, showing potential as a treatment for benign prostatic hyperplasia.

Contribution

A novel compound with dual PDE4 and PDE5 inhibitory activity was synthesized and evaluated for BPH treatment.

Findings

Compound VIII inhibited PDE5 and two PDE4 isoforms in biochemical assays.

It relaxed prostate tissue and reduced cell proliferation in human hyperplastic prostate cells.

Molecular docking explained the compound's interaction with PDE5A.

Abstract

Benign prostatic hyperplasia (BPH) is a prevalent condition
in
aging men that negatively affects the quality of life. Current therapeutic
strategies aim to reduce prostate size and smooth muscle contraction.
In this study, five novel 4-oxazoline-centered compounds with potential
phosphodiesterase (PDE) inhibitory activity were synthesized and tested
for biochemical and pharmacological effects in isolated prostate cells
and tissues. Among them, compound VIII exhibited inhibitory activity
against PDE5 and two PDE4 isoforms in cell-free assays. Additionally,
it relaxed isolated rat prostate tissue, enhanced nitric oxide-induced
relaxation, and reduced contractile responses mediated by alpha-1
adrenoceptors. Moreover, compound VIII significantly inhibited the
proliferation of a human hyperplastic prostate cell line, mimicking
the effects of rolipram, a PDE4 inhibitor. With its dual inhibition
of PDE4 and PDE5 and its ability to decrease both contraction and
cell proliferation, compound VIII emerges as a promising candidate
for further investigation as a potential treatment for BPH. Complementary
molecular docking and conformational analyses provided a structural
rationale for the observed activity trends, highlighting the role
of hydroxyethyl substituent interactions with the PDE5A H-loop in
modulating inhibitory potency. Taken together, the dual PDE4/PDE5
inhibition profile of compound VIII, combined with its favorable functional
effects on smooth muscle tone and cell proliferation, identifies this
scaffold as a promising starting point for further optimization toward
BPH therapy.

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