HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.

Johan Evenäs; Fredrik Edfeldt; Matti Lepistö; Naila Svitacheva; Anna Synnergren; Britta Lundquist; Mia Gränse; Anna Rönnholm; Mikael Varga; John Wright; Min Wei; Sherrie Yue; Junfeng Wang; Chong Li; Xuan Li; Gang Chen; Yong Liao; Gang Lv; Ann Tjörnebo; Frank Narjes

doi:10.1016/j.bmcl.2014.01.050

HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.

Johan Evenäs, Fredrik Edfeldt, Matti Lepistö, Naila Svitacheva, Anna Synnergren, Britta Lundquist, Mia Gränse, Anna Rönnholm, Mikael Varga, John Wright, Min Wei, Sherrie Yue, Junfeng Wang, Chong Li, Xuan Li, Gang Chen, Yong Liao, Gang Lv, Ann Tjörnebo, Frank Narjes

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

Sammanfattning

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.

Originalspråk	engelska
Sidor (från-till)	1315-1321
Tidskrift	Bioorganic & Medicinal Chemistry Letters
Volym	24
Nummer	5
DOI	https://doi.org/10.1016/j.bmcl.2014.01.050
Status	Published - 2014
Externt publicerad	Ja

Ämnesklassifikation (UKÄ)

Immunologi inom det medicinska området

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10.1016/j.bmcl.2014.01.050

http://www.ncbi.nlm.nih.gov/pubmed/24508129?dopt=Abstract

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Evenäs, J., Edfeldt, F., Lepistö, M., Svitacheva, N., Synnergren, A., Lundquist, B., Gränse, M., Rönnholm, A., Varga, M., Wright, J., Wei, M., Yue, S., Wang, J., Li, C., Li, X., Chen, G., Liao, Y., Lv, G., Tjörnebo, A., & Narjes, F. (2014). HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase. Bioorganic & Medicinal Chemistry Letters, 24(5), 1315-1321. https://doi.org/10.1016/j.bmcl.2014.01.050

@article{5a4f47208d8d4e238d0395feb4a534b3,

title = "HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.",

abstract = "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.",

author = "Johan Even{\"a}s and Fredrik Edfeldt and Matti Lepist{\"o} and Naila Svitacheva and Anna Synnergren and Britta Lundquist and Mia Gr{\"a}nse and Anna R{\"o}nnholm and Mikael Varga and John Wright and Min Wei and Sherrie Yue and Junfeng Wang and Chong Li and Xuan Li and Gang Chen and Yong Liao and Gang Lv and Ann Tj{\"o}rnebo and Frank Narjes",

year = "2014",

doi = "10.1016/j.bmcl.2014.01.050",

language = "English",

volume = "24",

pages = "1315--1321",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier",

number = "5",

}

Evenäs, J, Edfeldt, F, Lepistö, M, Svitacheva, N, Synnergren, A, Lundquist, B, Gränse, M, Rönnholm, A, Varga, M, Wright, J, Wei, M, Yue, S, Wang, J, Li, C, Li, X, Chen, G, Liao, Y, Lv, G, Tjörnebo, A & Narjes, F 2014, 'HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.', Bioorganic & Medicinal Chemistry Letters, vol. 24, nr. 5, s. 1315-1321. https://doi.org/10.1016/j.bmcl.2014.01.050

HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase. / Evenäs, Johan; Edfeldt, Fredrik; Lepistö, Matti et al.
I: Bioorganic & Medicinal Chemistry Letters, Vol. 24, Nr. 5, 2014, s. 1315-1321.

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

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 & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 5

ER -

HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.

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Ämnesklassifikation (UKÄ)

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