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.
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.
Duplantier
Allen J
AJ
Pfizer Global Research and Development, Groton, Connecticut 06340, USA. allen.j.duplantier@pfizer.com
Bachert
Elizabeth L
EL
Cheng
John B
JB
Cohan
Victoria L
VL
Jenkinson
Teresa H
TH
Kraus
Kenneth G
KG
McKechney
Michael W
MW
Pillar
Joann D
JD
Watson
John W
JW
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004285:Dogs; D004804:Eosinophils / Q000201:enzymology*; D005260:Female; D005289:Ferrets; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014839:Vomiting / Q000139:chemically induced
D006575:Heterocyclic Compounds, 3-Ring; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011994:Recombinant Proteins; D014230:Triazoles; C517806:tofimilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4