BMS-708163

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种有效的、选择性的、口服生物可利用的 γ-分泌酶抑制剂，Aβ40 IC50 为 3.0 nM。

A potent, selective and orally bioavailable inhibitor of γ-secretase with Aβ40 IC50 of 3.0 nM; demonstrates 193-fold selectivity against Notch; significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. Alzheimer's Disease Phase 2 Discontinued(In Vitro):Avagacestat (BMS-708163) exhibits weaker potency for inhibition of Notch processing, IC50=58±23 nM, as compared to its inhibition potency for APP cleavage. Avagacestat (BMS-708163) (10?μM) combined with gefitinib significantly attenuates the colony growth of PC9/AB2 cells, increases the expression of active caspase 3 and PARP and reduces the expression of Ki-67 in PC9/AB2 cells. Avagacestat (BMS-708163) induces apoptosis and enhances cell cycle arrest at the G1 phase in PC9/AB2 cells. Avagacestat (BMS-708163) treatment effectively downregulates the expression of Notch1, HES1, PI3K and Akt in PC9/AB2 cells. (In Vivo):Avagacestat (BMS-708163) significantly reduces both plasma and brain Aβ40 levels relative to control at 10 and 100 mg/kg for the entire dosing interval, demonstrates significant Aβ40 lowering for 8 h after an oral dose of 1 mg/kg, and significantly lowers CSF Aβ40 levels in rats, when measured 5 h after single oral doses ranging from 3 to 100 mg/kg. Avagacestat (BMS-708163) (10?mg/kg) monotherapy has a minor inhibitory effect on PC9/AB2 tumor growth compared with gefitinib alone. BMS-708163 monotherapy results in a slight increase in caspase 3 expression as well as a mild decrease in Ki-67 expression in vivo. In the xenograft lung cancer samples treated with Avagacestat (BMS-708163) plus gefitinib, there are a marked increase in caspase 3 expression and a reduction in Ki-67 staining.

Avagacestat (BMS-708163) exhibits weaker potency for inhibition of Notch processing, IC50=58±23 nM, as compared to its inhibition potency for APP cleavage. Avagacestat (BMS-708163) (10?μM) combined with gefitinib significantly attenuates the colony growth of PC9/AB2 cells, increases the expression of active caspase 3 and PARP and reduces the expression of Ki-67 in PC9/AB2 cells. Avagacestat (BMS-708163) induces apoptosis and enhances cell cycle arrest at the G1 phase in PC9/AB2 cells. Avagacestat (BMS-708163) treatment effectively downregulates the expression of Notch1, HES1, PI3K and Akt in PC9/AB2 cells.

Avagacestat (BMS-708163) significantly reduces both plasma and brain Aβ40 levels relative to control at 10 and 100 mg/kg for the entire dosing interval, demonstrates significant Aβ40 lowering for 8 h after an oral dose of 1 mg/kg, and significantly lowers CSF Aβ40 levels in rats, when measured 5 h after single oral doses ranging from 3 to 100 mg/kg. Avagacestat (BMS-708163) (10?mg/kg) monotherapy has a minor inhibitory effect on PC9/AB2 tumor growth compared with gefitinib alone. BMS-708163 monotherapy results in a slight increase in caspase 3 expression as well as a mild decrease in Ki-67 expression in vivo. In the xenograft lung cancer samples treated with Avagacestat (BMS-708163) plus gefitinib, there are a marked increase in caspase 3 expression and a reduction in Ki-67 staining.

Avagacestat

Wnt/Notch/Hedgehog

γ-secretase

γsecretase(Aβ40)|γsecretase(Aβ42)

Neurological Disease

Alzheimer Disease

1146699-66-2

520.885

C20H17ClF4N4O4S

>98% (HPLC)

10 mM in DMSO

O=C(N)[C@H](N(CC1=CC=C(C2=NOC=N2)C=C1F)S(=O)(C3=CC=C(Cl)C=C3)=O)CCC(F)(F)F

Pentanamide, 2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoro-, (2R)-

(-20℃)

With Ice Pack

≥ 2 years