SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase.

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.

• Authors: Allen J Duplantier, Elizabeth L Bachert, John B Cheng, Victoria L Cohan, Teresa H Jenkinson, Kenneth G Kraus, Michael W McKechney, Joann D Pillar, John W Watson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 2 Pg. 344-9 (Jan 25 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17228876 (Publication Type: Journal Article)

Chemical References

• Heterocyclic Compounds, 3-Ring
• Isoenzymes
• Phosphodiesterase Inhibitors
• Pyrazoles
• Pyridines
• Recombinant Proteins
• Triazoles
• tofimilast
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (chemistry, metabolism)
• Animals
• Biological Availability
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Dogs
• Eosinophils (enzymology)
• Female
• Ferrets
• Heterocyclic Compounds, 3-Ring (chemical synthesis, pharmacokinetics, pharmacology)
• Humans
• In Vitro Techniques
• Isoenzymes (chemistry, metabolism)
• Male
• Phosphodiesterase Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Pyrazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Pyridines (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Recombinant Proteins (chemistry)
• Structure-Activity Relationship
• Triazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Vomiting (chemically induced)