| Identification | Back Directory | [Name]
(3S)-3-amino-1-hydroxy-1,2,3,4-tetrahydroquinolin-2-one | [CAS]
34783-48-7 | [Synonyms]
PF-04859989
PE-04859989
PF 04859989,PF04859989
(3S)-3-amino-1-hydroxy-1,2,3,4-tetrahydroquinolin-2-one
2(1H)-Quinolinone, 3-amino-3,4-dihydro-1-hydroxy-, (3S)- | [EINECS(EC#)]
808-880-5 | [Molecular Formula]
C9H10N2O2 | [MDL Number]
MFCD18633107 | [MOL File]
34783-48-7.mol | [Molecular Weight]
178.19 |
| Hazard Information | Back Directory | [Uses]
PF-04859989 is a brain-penetrant, irreversible?kynurenine aminotransferase (KAT) II?inhibitor with?IC50s of 23 and 263 nM for hKAT II and rKAT II. PF-04859989 is selective for KAT II over human KAT I, KAT III, and KAT IV (IC50s of 22, 11, and >50 μM, respectively)[1]. | [Enzyme inhibitor]
This systemically available KAT II inhibitor (FW = 178.19 g/mol; CAS 34783-48-7; IUPAC: (3S)-3-amino-1-hydroxy-3,4-dihydroquinolin-2(1H)- one) irreversibly inhibits kynurenine amino transferase II, or KAT II, with Ki = 23 nM, kinact/Ki 112,000 M–1 s –1 , IC50 = 263 nM, and PartitionCoefficientn-octanol/H2O = 3 x 108. This inhibitor most likely makes an enamine adduct with enzyme-bound pyridoxal-P. Rationale: Kynurenate is a tryptophan-derived endogenous antagonist for glutamate and a7-nicotinic acetylcholine receptors in the brain. Increased levels are observed postmortem in the brains of patients with a range of neurocognitive disorders, including schizophrenia. Kynurenate may well contribute to the cognitive symptoms of these conditions. Pharmacology: PF-04859989 restores glutamate release "transients" evoked by ejections of nicotine into the prefrontal cortex of rats exhibiting elevated kynurenate levels. Systemic administration of PF-04859989 30 min prior to administration of Lkynurenine (but not when administered 30 min after L-kynurenine) restores glutamatergic transients recorded up to 120 min after the administration of the KAT II inhibitor. Furthermore, the KAT-II inhibitor significantly reverses L-kynurenine-induced elevations of brain KYNA levels. The KATII inhibitor does not affect nicotine-evoked glutamatergic transients in rats not pre-treated with L-kynurenine | [in vivo]
In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc)[1].
Rats receiving PF-04859989 (5 mg/kg; i.p.) exhibited a significantly lower number of spontaneously active DA neurons pertrack[1]. | Animal Model: | Male Sprague-Dawley rats[2] | | Dosage: | 5 mg/kg | | Administration: | I.p. | | Result: | Exhibited a significantly lower number of spontaneously active dopamine (DA) neurons pertrack compared to controls.
|
| [References]
[1] "Amy B Dounay, et al. Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia. ACS Med Chem Lett
. 2012 Jan 25;3(3):187-92." DOI:10.1021/ml200204m
[2] Linderholm KR, et al. Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons. Neuropharmacology. 2016;102:42-47. DOI:10.1016/j.neuropharm.2015.10.028 |
|
| Company Name: |
ChemCell Biomedicine Co.,Ltd.
|
| Tel: |
020-13556033878 2965585218 13556033878 |
| Website: |
www.chemicalbook.com/ShowSupplierProductsList15061/0_EN.htm |
|