GNE-3511 是一种生物可利用性和脑渗透dual leucine zipper kinase (DLK)抑制剂，具有口服活性，其Ki值为 0.5 nM。GNE-3511 可穿过血脑屏障，被用于神经退行性疾病的研究。
| 生物活性 | GNE-3511 is an orally active bioavailable and brain-penetrantdual leucine zipper kinase (DLK)inhibitor with aKiof 0.5 nM. GNE-3511 can cross the blood-brain-barrier and can be used for the research of neurodegenerative diseases[1]. |
| IC50& Target | Ki: 0.5 nM (DLK); IC50: 30 nM (p-JNK), 107 nM (DRG); ＞5000 nM (MKK4), ＞5000 nM (MKK7), 129 nM (JNK1),514 nM (JNK2), 364 nM (JNK3), 67.8 nM (MLK1), 767 nM (MLK2) and 602 nM (MLK3)[1] |
体外研究
(In Vitro) | GNE-3511 has inhibitory activity for p-JNK and DRG with IC50values of 30 nM and 107 nM, respectively[1].
GNE-3511 has kinase selectivity for MKK4, MKK7, JNK1, JNK2, JNK3, MLK1, MLK2 and MLK3 with IC50values of ＞5000 nM, ＞5000 nM, 129 nM, 514 nM, 364 nM, 67.8 nM, 767 nM and 602 nM, respectively[1].
GNE-3511 displays concentration-dependent protection of neurons from degeneration in vitro[1].
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体内研究
(In Vivo) | GNE-3511 (oral gavage; 75 mg/kg; single) suppresses CYP-induced nociceptive behavior by inhibiting DLK in mice[2].
GNE-3511 (oral gavage; 75 mg/kg; single) suppresses CYP-induced edema and hemorrhage in mouse bladder[2].
GNE-3511 (iv.; 1 mg/kg or po.; 5 mg/kg) exhibits moderate in vivo plasma clearances, moderate volumes of distribution, short half-lives, and brain penetration[2].
Pharmacokinetic Parameters of GNE-3511 (iv.; 1 mg/kg or po.; 5 mg/kg)[2].
| species | CLp(mL/min/kg | Vdss(L/kg | t1/2(h) | F (%) | Bu/Pu | CSF/Pu | | mouse | 56 | 2.5 | 0.6 | 45 | 0.24 at 6 h | | | rat | 30 | 3.7 | 1.8 | 63 | 0.7 | 0.4 | | dog | 41 | 6.5 | 4 | 32 | | 0.4 | | cynomolgous | 16 | 3.1 | 2.4 | 19 | | 0.6 | |
| Animal Model: | Cystitis mouse model[1] | | Dosage: | 75 mg/kg | | Administration: | oral gavage;75 mg/kg; single | | Result: | Significantly reduced the number of nociceptive behavior as well as nociceptive score.
Had no impact on bladder weight, did not induce bladder edema or hemorrhage and significantly suppressed CYP-induced increase in bladder weight, bladder edema, and hemorrhage. |
| Animal Model: | mouse, rat, cynomolgus and dog[2] | | Dosage: | 1 mg/k, 5 mg/kg | | Administration: | iv.; 1 mg/kg or po.; 5 mg/kg | | Result: | Exhibited moderate in vivo plasma clearances, moderate volumes of distribution, short half-lives and brain penetration. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 31.25 mg/mL(70.94 mM;Need ultrasonic) 配制储备液 | 1 mM | 2.2702 mL | 11.3510 mL | 22.7020 mL | | 5 mM | 0.4540 mL | 2.2702 mL | 4.5404 mL | | 10 mM | 0.2270 mL | 1.1351 mL | 2.2702 mL |
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