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

[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...

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Published inBioorganic & 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
LanguageEnglish
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
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Abstract [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.
AbstractList 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.
[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.
ArticleNumber 128115
Author Tsuboi, Katsunori
Nakatsuji, Yoshie
Deai, Yoko
Kassai, Momoe
Kimura, Hidenori
Isobe, Yoshiaki
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  email: yoshiaki-isobe@ds-pharma.co.jp
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CitedBy_id crossref_primary_10_1016_j_tips_2023_04_006
crossref_primary_10_1002_jcp_30876
crossref_primary_10_1002_slct_202104184
crossref_primary_10_1021_acs_jced_2c00794
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Keywords Brain permeable
R6/2
KYNA
BBB
Kynurenine monooxygenase
3-HK
KMO
Huntington's disease
Kynurenine pathway
3-HYDROXYKYNURENINE
2
R6
PATHWAY
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Snippet [Display omitted] Kynurenine monooxygenase (KMO) is expected to be a good drug target to treat Huntington’s disease (HD). This study presents the...
Kynurenine monooxygenase (KMO) is expected to be a good drug target to treat Huntington's disease (HD). This study presents the structure-activity relationship...
Source Web of Science
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StartPage 128115
SubjectTerms 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
Title 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
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https://www.ncbi.nlm.nih.gov/pubmed/34015507
Volume 44
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