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.
authors: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden. Electronic address: johan.evenas@redglead.com.
authors: Johan
authors: J
authors: Evenäs
authors: Discovery Science, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors: Fredrik
authors: F
authors: Edfeldt
authors: Department of Medicinal Chemistry, Respiratory Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors: Matti
authors: M
authors: Lepistö
authors: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors: Naila
authors: N
authors: Svitacheva
authors: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors: Anna
authors: A
authors: Synnergren
authors: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors: Britta
authors: B
authors: Lundquist
authors: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors: Mia
authors: M
authors: Gränse
authors: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors: Anna
authors: A
authors: Rönnholm
authors: Department of Medicinal Chemistry, Respiratory Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors: Mikael
authors: M
authors: Varga
authors: Department of Medicinal Chemistry, DMPK and Biology, BioDuro, Life Science Park Road Bld 2, Beijing 102206, PR China.
authors: John
authors: J
authors: Wright
authors: Department of Medicinal Chemistry, DMPK and Biology, BioDuro, Life Science Park Road Bld 2, Beijing 102206, PR China.
authors: Min
authors: M
authors: Wei
authors: Department of Medicinal Chemistry, DMPK and Biology, BioDuro, Life Science Park Road Bld 2, Beijing 102206, PR China.
authors: Sherrie
authors: S
authors: Yue
authors: Department of Medicinal Chemistry, DMPK and Biology, BioDuro, Life Science Park Road Bld 2, Beijing 102206, PR China.
authors: Junfeng
authors: J
authors: Wang
authors: Department of Medicinal Chemistry, DMPK and Biology, BioDuro, Life Science Park Road Bld 2, Beijing 102206, PR China.
authors: Chong
authors: C
authors: Li
authors: Department of Medicinal Chemistry, DMPK and Biology, BioDuro, Life Science Park Road Bld 2, Beijing 102206, PR China.
authors: Xuan
authors: X
authors: Li
authors: Department of Medicinal Chemistry, DMPK and Biology, BioDuro, Life Science Park Road Bld 2, Beijing 102206, PR China.
authors: Gang
authors: G
authors: Chen
authors: Department of Medicinal Chemistry, DMPK and Biology, BioDuro, Life Science Park Road Bld 2, Beijing 102206, PR China.
authors: Yong
authors: Y
authors: Liao
authors: Discovery Science, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors: Gang
authors: G
authors: Lv
authors: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors: Ann
authors: A
authors: Tjörnebo
authors: Department of Medicinal Chemistry, Respiratory Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: Frank.Narjes@astrazeneca.com.
authors: Frank
authors: F
authors: Narjes
mesh_terms: D000818:Animals; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006074:Gout Suppressants / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006207:Half-Life; D057166:High-Throughput Screening Assays; D033461:Hyperuricemia / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006074:Gout Suppressants; D011744:Pyrimidinones; D014969:Xanthine Oxidase
keywords: High-throughput screening; Hit-to-lead; Non-purine XO inhibitors; Pyrimidone; Xanthine oxidase