# Discovery of Marine-Inspired Guanidine-Based PDE4 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease

## TL;DR

This study discovers a new marine-inspired PDE4 inhibitor, B7, that effectively reduces inflammation in COPD and shows promise as a safer treatment option.

## Contribution

The development of novel marine-inspired PDE4 inhibitors using computer-aided drug design and their validation in COPD models.

## Key findings

- Compound B7 showed potent PDE4 inhibition and a favorable safety profile.
- B7 reduced inflammation and lung damage in a COPD rat model.
- B7 activates cAMP-PKA-CREB and suppresses NF-κB pathways to exert anti-inflammatory effects.

## Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory disorder with a globally increasing prevalence. Current therapeutic strategies are limited by drug resistance and safety concerns. Studies suggest that inhibiting the secretion of inflammatory cytokines represents a promising approach for COPD treatment. Phosphodiesterase-4 (PDE4) inhibitors have emerged as potent anti-inflammatory agents for respiratory diseases. In this study, we integrated a marine-derived natural product with computer-aided drug design to develop 32 novel PDE4 inhibitors. Compound B7 exhibited potent PDE4 inhibitory activity and a favorable safety profile. In rat model of COPD, B7 significantly reduced inflammatory cell infiltration and cytokine levels, ameliorated pathological changes in the lung, decreased the percentage of goblet cell positivity, and reduced expiratory resistance. Furthermore, in vitro mechanistic studies revealed that B7 exerts its anti-inflammatory effects by activating the cAMP-PKA-CREB signaling pathway and suppressing the NF-κB pathway in RAW264.7 cells. In conclusion, B7 demonstrates potential as a safe and effective PDE4-targeted candidate for the treatment of COPD.