Discovery of 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051 - a xanthine oxidoreductase inhibitor for the treatment of hyperuricemia [corrected].
Our previous study identified 2-[2-(2-methoxyethoxy)ethoxy]-5-[5-(2-methyl-4-pyridyl)-1H-[1,2,4] triazol-3-yl]benzonitrile (2)[corrected]as a safe and potent xanthine oxidoreductase (XOR) inhibitor for the treatment of hyperuricemia. Here, we synthesized a series of 3,5-dipyridyl-1,2,4-triazole derivatives and, in particular, examined their in vivo activity in lowering the serum uric acid levels in rats. As a result, we identified 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole (FYX-051, compound 39) [corrected] to be one of the most potent XOR inhibitors; it exhibited an extremely potent in vivo activity, weak CYP3A4-inhibitory activity and a better pharmacokinetic profile than compound 2. Compound 39 is currently being evaluated in a phase 2 clinical trial.
Sato
Takahiro
T
Research Laboratories 1, Research Department, Medical R&D Division, Fuji Yakuhin Co., Ltd, 3936-2 Sashiougi, Nishi-ku, Saitama-shi, Saitama 331-0047, Japan. takahiro@fujiyakuhin.co.jp
Ashizawa
Naoki
N
Matsumoto
Koji
K
Iwanaga
Takashi
T
Nakamura
Hiroshi
H
Inoue
Tsutomu
T
Nagata
Osamu
O
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D033461:Hyperuricemia / Q000188:drug therapy*; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D009570:Nitriles; D011725:Pyridines; C504882:FYX-051; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014968:Xanthine Dehydrogenase