BMS-708163

SKU: orb1226915

Description

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.\n(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.

Key Properties

• CAS Number: 1146699-66-2
• MW: 520.885
• Purity: >98% (HPLC)
• Formula: C₂₀H₁₇ClF₄N₄O₄S
• SMILES: 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
• Target: γ-secretase
• Solubility: 10 mM in DMSO

Bioactivity

• 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.
• 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.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

Avagacestat

Quick Database Links

Gene Symbol

γ-secretase