ABSTRACT
Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC50 = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a, originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent.
Subject(s)
Inflammatory Bowel Diseases , Phosphodiesterase 4 Inhibitors , Aminopyridines , Animals , Benzamides , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Cyclopropanes , Dextran Sulfate , Dipyridamole/therapeutic use , Dogs , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/drug therapy , Mice , Phosphodiesterase 4 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/therapeutic useABSTRACT
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 18a with potent inhibitory affinity (IC50 = 4.2 nM), favorable physico-chemical properties, and a different binding pattern from roflumilast. Emetic activity tests on dogs demonstrated that 18a 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 18a (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.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/therapeutic use , Idiopathic Pulmonary Fibrosis/drug therapy , Phosphodiesterase 4 Inhibitors/therapeutic use , A549 Cells , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Dogs , Epithelial-Mesenchymal Transition/drug effects , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/metabolism , Humans , Idiopathic Pulmonary Fibrosis/pathology , Lung/drug effects , Lung/pathology , Male , Molecular Structure , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/metabolism , Protein Binding , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
OBJECTIVE: To develop measurement and control system for human centrifuge to simulate arbitrary hypergravity curves. METHOD: The human centrifuge is controlled by the upper and lower level computers. The measurement and control computer is as upper, and the real-time controller as lower. RESULT: The system performance could satisfy the requirement of the human centrifuge. CONCLUSION: The measurement and control system can achieve a high control precision. It is safe, reliable and easy to operate.
