title: 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.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340, USA. allen.j.duplantier@pfizer.com
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Duplantier
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Bachert
authors.forename: John B
authors.initials: JB
authors.lastname: Cheng
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Cohan
authors.forename: Teresa H
authors.initials: TH
authors.lastname: Jenkinson
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Kraus
authors.forename: Michael W
authors.initials: MW
authors.lastname: McKechney
authors.forename: Joann D
authors.initials: JD
authors.lastname: Pillar
authors.forename: John W
authors.initials: JW
authors.lastname: Watson
mesh_terms: 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
chemical_list: 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