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Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors
- Source :
- Bioorganic & Medicinal Chemistry. 25:5709-5717
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Improvement of subtype selectivity of an inhibitor's binding activity using the conformational restriction approach has become an effective strategy in drug discovery. In this study, we applied this approach to PDE4 inhibitors and designed a series of novel oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally restricted analogues of rolipram. The bioassay results demonstrated the oxazolidinone-fused tetrahydroisoquinoline derivatives exhibited moderate to good inhibitory activity against PDE4B and high selectivity for PDE4B/PDE4D. Among these derivatives, compound 12 showed both the strongest inhibition activity (IC50=0.60μM) as well as good selectivity against PDE4B and good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary SAR study showed that restricting the conformation of the catechol moiety in rolipram with the scaffold of oxazolidinone-fused tetrahydroisoquinoline could lead to an increase in selectivity for PDE4B over PDE4D, which was consistent with the observed docking simulation.
- Subjects :
- 0301 basic medicine
Stereochemistry
Clinical Biochemistry
Molecular Conformation
Pharmaceutical Science
01 natural sciences
Biochemistry
Inhibitory Concentration 50
Pulmonary Disease, Chronic Obstructive
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
PDE4B
In vivo
Sepsis
Tetrahydroisoquinolines
Drug Discovery
medicine
Animals
Humans
Molecular Biology
Rolipram
Tetrahydroisoquinoline
Drug discovery
Organic Chemistry
Rational design
Asthma
Cyclic Nucleotide Phosphodiesterases, Type 4
0104 chemical sciences
Molecular Docking Simulation
Disease Models, Animal
010404 medicinal & biomolecular chemistry
030104 developmental biology
chemistry
Docking (molecular)
Drug Design
Molecular Medicine
Phosphodiesterase 4 Inhibitors
Selectivity
medicine.drug
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....75a149f929f1cf270e46165b1f2f38d5