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SB-649868

CAS No. : 380899-24-1

MCE 站：SB-649868

产品活性：SB-649868 是一种口服有效的选择性食欲素 OX1 和 OX 2 受体拮抗剂 (作用于 OX1 和 OX2 受体，pK_i 分别为 9.4 和 9.5)。

研究领域：GPCR/G Protein  |  Neuronal Signaling

作用靶点：Orexin Receptor (OX Receptor)

In Vitro: SB-649868 is identified as one the most in vitro potent dual OX₁ and OX₂ receptor antagonist known at that time (pK_i=9.4 and 9.5 at the OX₁ and OX₂ receptor, respectively) . SB-649868 antagonizes orexin-A-induced inositol 1 phosphate (IP1) accumulation with the following pK_B value (OX₁=9.67; OX₂=9.64). SB-649868 displaces the [³H]ACT-078573 receptor binding with the following pKi values: OX₁=9.27; OX₂=8.91. Increasing concentrations of SB-649868 (0.3 nM-30 nM) induces a rightward shift of the orexin-A CRCs with a depression of the agonist efficacy suggesting a clear non-surmountable behavior. The calculated apparent pK_b values are 9.67±0.03 and 9.64±0.07 for OX₁ and OX₂.

In Vivo: Pharmacokinetic studies in the male CD rat, performed at 1 mg/kg, iv and 3 mg/kg, po, demonstrate an excellent pharmacokinetic profile for a hypnotic agent featuring moderate clearance in plasma (Cl_p=24 mL/min/kg), short half-life of (<0.6 h) and a low volume of distribution (V_ss=1.1 l/kg), coupled with excellent oral bioavailability (F=85%) and good exposure in plasma (C_max=333 ng/mL). A brain to blood ratio (B/B) of 0.1:1 is observed 1 h after iv administration, a value in line with the expected partition between the two compartments based on the lower tissue binding observed in vitro in brain tissues (fraction unbound/brain=5.28%) with respect to plasma proteins (fraction unbound/plasma=1.34%). SB-649868, administered orally 3 h before OX-A injection at doses of 1, 3 and 10 mg/kg, causes a dose-dependent reduction of OX-A induced grooming as measured by total time spent grooming and number of grooming bouts (p <0.01 at 3 and 10 mg/kg po) . From dissociation kinetic studies using [³H]ACT-078573, the calculated long half-life, (t_1/2) supports the non-surmountability profile of SB-649868 (t_1/2=35.91 min) at OX₁ orexin receptor. The long or moderately long t_1/2values for SB-649868 at OX₂ orexin receptor (t_1/2=8.09 min).

相关产品：Drug Repurposing Compound Library Plus  |  Clinical Compound Library Plus  |  Bioactive Compound Library Plus  |  Orexin A (human, rat, mouse)  |  TCS-OX2-29  |  GSK1059865  |  SB-674042  |  TCS 1102  |  EMPA  |  SB-408124  |  Orexin B, human TFA  |  IPSU  |  Orexin B, rat, mouse  |  Orexin receptor antagonist 2  |  OXA(17-33)  |  [Ala11,D-Leu15]-Orexin B(human)

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