9VVE

Inhibition of PDE4 by Inhaled Small Molecules in COPD

This is a non-PDB format compatible entry.

Summary for 9VVE

• Entry DOI: 10.2210/pdb9vve/pdb
• Descriptor: 3',5'-cyclic-AMP phosphodiesterase 4B, 2-[3,5-bis(chloranyl)pyridin-4-yl]-1-(2-chloranyl-8-methoxy-quinolin-5-yl)ethanone, ZINC ION, ... (4 entities in total)
• Functional Keywords: pde4 inhibition, small molecules, copd therapy, inhalation, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 87648.02

Authors

Bi, Y.C. (deposition date: 2025-07-15, release date: 2026-05-27)

Primary citation

Xing, G.,Bi, Y.,Li, Z.,Zhi, Z.,Li, H.,Cheng, M.
Discovery, Synthesis, and Biological Evaluation of Novel Quinoline-Based PDE4 Inhibitors with Potent Anti-Chronic Obstructive Pulmonary Disease Activity.
J.Med.Chem., 69:3852-3867, 2026

PubMed Abstract: Phosphodiesterase 4 (PDE4) is a key target for COPD anti-inflammatory drugs. The approved oral PDE4 inhibitor for COPD causes side effects such as nausea and vomiting due to high systemic exposure. Developing highly selective PDE4 inhibitors suitable for inhaled delivery represents an effective alternative strategy. Herein, we report the identification of P29, a PDE4 inhibitor exhibiting picomolar inhibitory potency (IC = 0.019 nM) and high selectivity (>10,000) over other PDEs. Subsequent studies demonstrated that P29 effectively suppressed LPS-induced TNF-α release in PBMCs. Notably, the fractions absorbed via pulmonary deposition and orally absorbed fractions were rapidly metabolized, reducing systemic exposure and minimizing adverse reactions. P29 significantly improved pulmonary function, inhibited inflammatory cell activity, reduced release of inflammatory cytokines, and ameliorated lung tissue damage in rat models of COPD induced by cigarette smoke and LPS. Collectively, our data highlight the therapeutic potential of P29 in COPD.

PubMed: 41644131
DOI: 10.1021/acs.jmedchem.5c02775

Experimental method

X-RAY DIFFRACTION (3.51 Å)