Abstract
By studying the co-crystal information of interactions between PDE5 and its inhibitors, forty new tetrahydro-β-carbolines based-analogues were synthesized, and tested for their PDE5 inhibition. Some compounds were as active as tadalafil in inhibiting PDE5 and of better selectivity profile particularly versus PDE11A, the nature of the terminal ring and its nitrogen substituent are the main determinants of selectivity. Ensemble docking confirmed the role of H-loop closed conformer in activity versus its occluded and open forms. Conformational studies showed the effect of bulkiness of the terminal ring N-alkyl substituent on the formation of stable enzyme ligands conformers. The difference in potencies of hydantoin and piperazinedione analogues, together with the necessity of C-5/C-6 R-absolute configuration has been revealed through molecular docking.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
MeSH terms
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3',5'-Cyclic-GMP Phosphodiesterases
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Carbolines / chemical synthesis*
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Carbolines / chemistry
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Cell Proliferation
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Cyclic Nucleotide Phosphodiesterases, Type 5 / chemistry*
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Diketopiperazines / chemical synthesis*
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Diketopiperazines / chemistry
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Drug Design
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Enzyme Assays
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Humans
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Hydantoins / chemical synthesis*
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Hydantoins / chemistry
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Hydrogen Bonding
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Inhibitory Concentration 50
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Kinetics
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Molecular Docking Simulation
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Phosphodiesterase 5 Inhibitors / chemical synthesis*
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Phosphodiesterase 5 Inhibitors / chemistry
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Phosphoric Diester Hydrolases / chemistry
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Protein Structure, Secondary
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
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Tadalafil
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Thermodynamics
Substances
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Carbolines
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Diketopiperazines
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Hydantoins
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Phosphodiesterase 5 Inhibitors
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Recombinant Proteins
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Tadalafil
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Phosphoric Diester Hydrolases
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3',5'-Cyclic-GMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 5
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PDE11A protein, human