MK-0359   Click here for help

GtoPdb Ligand ID: 9852

Synonyms: L-454,560 [1] | L-454560 | MK0359
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: MK-0359 is a potent and selective, oral PDE4 inhibitor that has a competitive and reversible mode of interaction. MK-0359 is identified as L-454,560 [1] by citation in [2]. MK-0359 inhibits both the apo- (Mg2+ free) and holoenzyme ((Mg2+-bound) states of PDE4 [1].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 0
Rotatable bonds 7
Topological polar surface area 136.85
Molecular weight 587.15
XLogP 6.09
No. Lipinski's rules broken 1
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Canonical SMILES Cc1noc(n1)C(=Cc1cccc(c1)c1cc(cc2c1nccc2)C(S(=O)(=O)C)(C)C)c1ccc(cc1)S(=O)(=O)C
Isomeric SMILES Cc1noc(n1)/C(=C/c1cccc(c1)c1cc(cc2c1nccc2)C(S(=O)(=O)C)(C)C)/c1ccc(cc1)S(=O)(=O)C
InChI InChI=1S/C31H29N3O5S2/c1-20-33-30(39-34-20)28(22-11-13-26(14-12-22)40(4,35)36)17-21-8-6-9-23(16-21)27-19-25(31(2,3)41(5,37)38)18-24-10-7-15-32-29(24)27/h6-19H,1-5H3/b28-17+
Bioactivity Comments
MK-0359 is active in vitro and in vivo [1]. It blocks LPS-induced TNF-α formation in whole blood assays with a potency similar to that exhibited by roflumilast. Evidence suggest that majority of the anti-inflammatory effect of PDE4 inhibition is through PDE4B and PDE4D isozymes, and that PDE4D, as the major isoform in the brain responsible for emesis [3], is associated with the adverse gastrointestinal (GI) events associated with PDE4 inhibition. MK-0359 inhibits the hydrolysis of cAMP by PDE4A, 4B and 4D with similar potencies, which accounts for the adverse GI effects observed in clinical trial [2].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
phosphodiesterase 4B Hs Inhibitor Inhibition 9.3 pIC50 - 1
pIC50 9.3 (IC50 5x10-10 M) [1]
phosphodiesterase 4D Hs Inhibitor Inhibition 8.9 pIC50 - 1
pIC50 8.9 (IC50 1.2x10-9 M) [1]
phosphodiesterase 4A Hs Inhibitor Inhibition 8.8 pIC50 - 1
pIC50 8.8 (IC50 1.6x10-9 M) [1]
phosphodiesterase 4C Hs Inhibitor Inhibition 8.0 pIC50 - 1
pIC50 8.0 (IC50 9.1x10-9 M) [1]