TY - JOUR
T1 - HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.
AU - Evenäs, Johan
AU - Edfeldt, Fredrik
AU - Lepistö, Matti
AU - Svitacheva, Naila
AU - Synnergren, Anna
AU - Lundquist, Britta
AU - Gränse, Mia
AU - Rönnholm, Anna
AU - Varga, Mikael
AU - Wright, John
AU - Wei, Min
AU - Yue, Sherrie
AU - Wang, Junfeng
AU - Li, Chong
AU - Li, Xuan
AU - Chen, Gang
AU - Liao, Yong
AU - Lv, Gang
AU - Tjörnebo, Ann
AU - Narjes, Frank
PY - 2014
Y1 - 2014
N2 - The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.
AB - The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.
U2 - 10.1016/j.bmcl.2014.01.050
DO - 10.1016/j.bmcl.2014.01.050
M3 - Article
C2 - 24508129
SN - 0960-894X
VL - 24
SP - 1315
EP - 1321
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 5
ER -