Target nature :
TrkB
CAS n° :
892748-58-2
Mecanism of action :
positive allosteric modulator (EC50 = 1.5 nM)
Physico-chemical properties :
aqueous solubility > 200 microM
Probe availability :
Laboratoire d'innovation thérapeutique (LIT), UMR7200 CNRS-Université de Strasbourg
Princeps reference :
TB001 is a selective positive allosteric modulator of the TrkB receptor tyrposine kinases. It potentiates the BNF-induced TrkB phosphorylation by 50% as well as all intracellular BNDF signaling pathways. It promotes BDNF-induced neurite outgrowth, neuronal survival and partially reverse Huntington disease phenotype (motor deficits, termors) by chronic administration to mice.
More bibliography :
TrkB positive allosteric modulators, WO2021/023858
Other available information on the probe :
storage: 4°C
stable in plasma
Other information on the target :
receptor of BDNF (brain derived neurotrophic factor)
Selectivity profile :
highly selective vs the kinome
2 off-targets identified in a safety screen (muscarinic M3 receptor: IC50=190 nM; Acetylcholinesterase: IC50=2.8 uM)
In vivo data :
BBB permation: [brain]/[plasma} = 0.37 after 3h (5 mg/kg, ip, mice)
reduces latency to fall (rotaroad test) and tremors in R6/2 mice (Huntinton disease phenotype) after 8 w chronic treatment (0.5 mg/kg ip oad)
In vitro data :
Protein binding (plasma, human): 47%
In vitro absorption: Caco-2: A-B permeability: 0.6.10-6 cm/s, B-A permeability: 2.3.10-6 cm/s
Intrinsic clearance (HLM), t1/2= 41 min
CYP inhibition @ 10uM
CYP1A inhibition (HLM, phenacetin substrate) 5.0 %
CYP2B6 inhibition (HLM, bupropion substrate) -0.5 %
CYP2C8 inhibition (HLM, paclitaxel substrate) 20.4 %
CYP2C9 inhibition (HLM, diclofenac substrate) -3.1 %
CYP2C19 inhibition (HLM, omeprazole substrate) 14.8 %
CYP2D6 inhibition (HLM, dextromethorphan substrate) 19.1 %
CYP3A inhibition (HLM, midazolam substrate) 1.4 %
CYP3A inhibition (HLM, testosterone substrate) 37.7 %
Toxicity :
maximum tolerated dose (MTD)= 20 mg/kg
no tox effects observed after 14j chronic adminstration to mice (MTD)
Chaine SMILES :
CN5CCN(c4ccc3nnc(CCC(=O)NC2CCN(Cc1ccccc1)CC2)n3n4)CC5
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