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.
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Duplantier AJ, Bachert EL, Cheng JB, Cohan VL, Jenkinson TH, Kraus KG, McKechney MW, Pillar JD, Watson JW
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.
J Med Chem. 2007 Jan 25;50(2):344-9.
- PubMed ID
- 17228876 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) (R)-Rolipram cAMP-specific 3',5'-cyclic phosphodiesterase 4B IC 50 (nM) 231 N/A N/A Details (R)-Rolipram cAMP-specific 3',5'-cyclic phosphodiesterase 4D IC 50 (nM) 622 N/A N/A Details Piclamilast cAMP-specific 3',5'-cyclic phosphodiesterase 4A IC 50 (nM) 4 N/A N/A Details Piclamilast cAMP-specific 3',5'-cyclic phosphodiesterase 4B IC 50 (nM) 3 N/A N/A Details Piclamilast cAMP-specific 3',5'-cyclic phosphodiesterase 4C IC 50 (nM) 14 N/A N/A Details Piclamilast cAMP-specific 3',5'-cyclic phosphodiesterase 4D IC 50 (nM) 2 N/A N/A Details