Abstract
The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / chemistry
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
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Animals
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Biological Availability
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Dogs
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Eosinophils / enzymology*
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Female
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Ferrets
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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In Vitro Techniques
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Male
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Phosphodiesterase Inhibitors / chemical synthesis*
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Phosphodiesterase Inhibitors / pharmacokinetics
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Phosphodiesterase Inhibitors / pharmacology
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Rats
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
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Triazoles / chemical synthesis*
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Triazoles / pharmacokinetics
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Triazoles / pharmacology
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Vomiting / chemically induced
Substances
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Heterocyclic Compounds, 3-Ring
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Isoenzymes
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Phosphodiesterase Inhibitors
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Pyrazoles
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Pyridines
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Recombinant Proteins
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Triazoles
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tofimilast
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4