N-(6-phenylpyridazin-3-yl)benzenesulfonamides as highly potent, brain-permeable, and orally active kynurenine monooxygenase inhibitors

Kimura, Hidenori; Suda, Hitoshi; Kassai, Momoe; Endo, Mika; Deai, Yoko; Yahata, Masahiro; Miyajima, Masayasu; Isobe, Yoshiaki

doi:10.1016/j.bmcl.2020.127753

Cited by 9 publications

(7 citation statements)

References 13 publications

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“…Compound 29 resulted in single nanomolar level efficacy and moderate brain exposure. Reducing tPSA is an effective strategy to improve BBB penetration …”

Section: Strategies For Enhancing the Bbb Permeability Or Reducing Th...mentioning

confidence: 99%

“…Reducing tPSA is an effective strategy to improve BBB penetration. 99 Zwicker et al recently revealed studies toward developing potent inhibitors of Toxoplasma gondii cathepsin L (TgCPL), a viable target for the treatment of parasitic infections. Lead compound 30 was an inhibitor of human cathepsin L (HsCPL), which had a high tPSA (tPSA = 97.6 Å 2 ).…”

Section: Strategies For Enhancing the Bbbmentioning

confidence: 99%

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Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

et al. 2021

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In the development of central nervous system (CNS) drugs, the blood–brain barrier (BBB) restricts many drugs from entering the brain to exert therapeutic effects. Although many novel delivery methods of large molecule drugs have been designed to assist transport, small molecule drugs account for the vast majority of the CNS drugs used clinically. From this perspective, we review studies from the past five years that have sought to modify small molecules to increase brain exposure. Medicinal chemists make it easier for small molecules to cross the BBB by improving diffusion, reducing efflux, and activating carrier transporters. On the basis of their excellent work, we summarize strategies for structural modification of small molecules to improve BBB penetration. These strategies are expected to provide a reference for the future development of small molecule CNS drugs.

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“…Compound 29 resulted in single nanomolar level efficacy and moderate brain exposure. Reducing tPSA is an effective strategy to improve BBB penetration …”

Section: Strategies For Enhancing the Bbb Permeability Or Reducing Th...mentioning

confidence: 99%

Section: Strategies For Enhancing the Bbbmentioning

confidence: 99%

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

et al. 2021

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“… 90 Furthermore, a brain permeable KMO inhibitor has been developed with potent effects, which is proposed to be used in a wide range of inflammatory neurological diseases. 91 The KMO inhibitors could also be tested for NASH and experience from the use of KMO inhibitors in neurological diseases may be helpful for NASH.…”

Section: Plausible Therapeutic Implicationsmentioning

confidence: 99%

Intestinal Dysbiosis, the Tryptophan Pathway and Nonalcoholic Steatohepatitis

Chen

Vitetta

Henson

et al. 2022

Int J�Tryptophan�Res

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Non-alcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH), which may then progress to the development of cirrhosis and hepatocarcinoma. NASH is characterized by both steatosis and inflammation. Control of inflammation in NASH is a key step for the prevention of disease progression to severe sequalae. Intestinal dysbiosis has been recognized to be an important causal factor in the pathogenesis of NASH, involving both the accumulation of lipids and aggravation of inflammation. The effects of gut dysbiosis are mediated by adverse shifts of various intestinal commensal bacterial genera and their associated metabolites such as butyrate, tryptophan, and bile acids. In this review, we focus on the roles of tryptophan and its metabolites in NASH in association with intestinal dysbiosis and discuss possible therapeutic implications.

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“…Inhibitors of KMO are of therapeutic interest due to their anticipated shift in the KP from neurotoxic to neuroprotective metabolites by limiting the production of 3-hydroxykynurenine, 3-hydroxyanthranillic acid, and quinolinic acid [ 1 ]. Additionally, KMO inhibitors may modulate the disease state by increasing the production of the neuroprotective product kynurenic acid [ 1 , 10 ]. A number of KMO inhibitors have been discovered, both similar and dissimilar to the enzyme substrate L-Kyn.…”

Section: Introductionmentioning

confidence: 99%

Gram-Scale Preparation of Cannflavin A from Hemp (Cannabis sativa L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-Monooxygenase

Puopolo

Chang

Liu

et al. 2022

Biology

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Inhibitors targeting kynurenine-3-monooxygenase (KMO), an enzyme in the neurotoxic kynurenine pathway (KP), are potential therapeutics for KP metabolites-mediated neuroinflammatory and neurodegenerative disorders. Although phytochemicals from Cannabis (C. sativa L.) have been reported to show modulating effects on enzymes involved in the KP metabolism, the inhibitory effects of C. sativa compounds, including phytocannabinoids and non-phytocannabinoids (i.e., cannflavin A; CFA), on KMO remain unknown. Herein, CFA (purified from hemp aerial material at a gram-scale) and a series of phytocannabinoids were evaluated for their anti-KMO activity. CFA showed the most active inhibitory effect on KMO, which was comparable to the positive control Ro 61-8048 (IC50 = 29.4 vs. 5.1 μM, respectively). Furthermore, a molecular docking study depicted the molecular interactions between CFA and the KMO protein and a biophysical binding assay with surface plasmon resonance (SPR) technique revealed that CFA bound to the protein with a binding affinity of . A competitive SPR binding analysis suggested that CFA and Ro 61-8048 bind to the KMO protein in a competitive manner. Our findings show that C. sativa derived phytochemicals, including CFA, are potential KMO inhibitors, which provides insight into the development of therapeutics targeting the KP and its related pathological conditions.

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N-(6-phenylpyridazin-3-yl)benzenesulfonamides as highly potent, brain-permeable, and orally active kynurenine monooxygenase inhibitors

Cited by 9 publications

References 13 publications

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

Intestinal Dysbiosis, the Tryptophan Pathway and Nonalcoholic Steatohepatitis

Gram-Scale Preparation of Cannflavin A from Hemp (Cannabis sativa L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-Monooxygenase

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