Discovery of N-(6-(5-fluoro-2-(piperidin-1-yl)phenyl)pyridazin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)methanesulfonamide as a brain-permeable and metabolically stable kynurenine monooxygenase inhibitor

• Published in: Bioorganic & medicinal chemistry letters Vol. 44; pp. 128115 - 128119
• Main Authors: Tsuboi, Katsunori, Kimura, Hidenori, Nakatsuji, Yoshie, Kassai, Momoe, Deai, Yoko, Isobe, Yoshiaki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.07.2021; Elsevier
• Subjects: 3-HK; Animals; BBB; Blood-Brain Barrier - drug effects; Brain permeable; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Humans; Huntington's disease; KMO; KYNA; Kynurenine 3-Monooxygenase - antagonists & inhibitors; Kynurenine 3-Monooxygenase - metabolism; Kynurenine monooxygenase; Kynurenine pathway; Life Sciences & Biomedicine; Mice; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; R6/2; Rats; Science & Technology; Structure-Activity Relationship; Brain permeable; R6/2; KYNA; BBB; Kynurenine monooxygenase; 3-HK; KMO; Huntington's disease; Kynurenine pathway; 3-HYDROXYKYNURENINE; 2; R6; PATHWAY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.128115

[Display omitted] Kynurenine monooxygenase (KMO) is expected to be a good drug target to treat Huntington’s disease (HD). This study presents the structure-activity relationship of pyridazine derivatives to find novel KMO inhibitors. The most promising compound 14 resolved the problematic issues of lead compound 1, i.e., metabolic instability and reactive metabolite-derived side-effects. Compound 14 exhibited high brain permeability and a long-lasting pharmacokinetics profile in monkeys, and neuroprotective kynurenic acid was increased by a single administration of 14 in R6/2 mouse brain. These results demonstrated 14 may be a potential drug candidate to treat HD.