SAR of a Series of 5,6-Dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-α]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.