The development of new triazole based inhibitors of tumor necrosis factor-alpha (TNF-alpha) production.
4-Aryl-5-pyridyl and 4-aryl-5-pyrimidyl based inhibitors of TNF-alpha production, which contain a novel triazole 5-member heterocyclic core, are described. Many pyridyl triazoles containing either an alkyl ether or a substituted aryl side chain on the triazole core showed sub-micromolar activity against LPS-induced TNF-alpha, while pyrimidyl triazoles containing an ethoxymethyl side chain exhibited even better inhibitory activity. Secondary screening data are presented for the pyrimidyl triazoles. Triazole 14e combined excellent potency with good oral bioavailability in the rat.
Tullis
Joshua S
JS
Array Biopharma, 3200 Walnut Street, Boulder, CO 80301, USA.
VanRens
John C
JC
Natchus
Michael G
MG
Clark
Michael P
MP
De
Biswanath
B
Hsieh
Lily C
LC
Janusz
Michael J
MJ
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D008070:Lipopolysaccharides; D011743:Pyrimidines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha