7F2L

Crystal structure of PDE4D catalytic domain complexed with compound 18a

Summary for 7F2L

• Entry DOI: 10.2210/pdb7f2l/pdb
• Descriptor: Isoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde4 inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 117099.70

Authors

Huang, Y.-Y.,He, X.,Luo, H.-B. (deposition date: 2021-06-11, release date: 2021-10-20, Last modification date: 2023-11-29)

Primary citation

Huang, Y.Y.,Deng, J.,Tian, Y.J.,Liang, J.,Xie, X.,Huang, Y.,Zhu, J.,Zhu, Z.,Zhou, Q.,He, X.,Luo, H.B.
Mangostanin Derivatives as Novel and Orally Active Phosphodiesterase 4 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis with Improved Safety.
J.Med.Chem., 64:13736-13751, 2021

PubMed Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, and its incidence rate is rapidly rising. However, effective therapies for the treatment of IPF are still lacking. Phosphodiesterase 4 (PDE4) inhibitors were reported to be potential anti-fibrotic agents, but their clinical use was hampered by side effects like emesis and nausea. Herein, structure-based hit-to-lead optimizations of natural mangostanin resulted in the novel and orally active PDE4 inhibitor with potent inhibitory affinity (IC = 4.2 nM), favorable physico-chemical properties, and a different binding pattern from roflumilast. Emetic activity tests on dogs demonstrated that cannot cause emesis even at an oral dose of 10 mg/kg, whereas rolipram had severe emetic effects at an oral dose of 1 mg/kg. Finally, the oral administration of (10 mg/kg) exhibited comparable anti-pulmonary fibrosis effects with pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model, indicating its potential as a novel anti-IPF agent with improved safety.

PubMed: 34520193
DOI: 10.1021/acs.jmedchem.1c01085

Experimental method

X-RAY DIFFRACTION (2.10111436093 Å)