| Description | (1S,2R)-Alicapistat ((1S,2R)-ABT-957) is a highly efficient, orally active compound that selectively inhibits human calpains 1 and 2, with promising implications for Alzheimer's disease (AD) therapy [1]. This compound effectively addresses the metabolic liability associated with carbonyl reduction, while demonstrating potent inhibition of calpain 1 with an IC50 value of 395 nM [2]. |
| In vitro | (1S,2R)-Alicapistat的中樞神經系統滲透濃度不足以達到藥理學效果[1]。Calpain 1（μ-calpain）和Calpain 2（m-calpain）的表達依賴鈣濃度，分別需要μ摩爾或m摩爾的鈣濃度來激活。"(1S,2R)-Alicapistat（100 nM）能防止Aβ寡聚體引起的大鼠突觸傳輸缺陷[2]。"(1S,2R)-Alicapistat（385 nM）在預防NMDA引起的神經退化和A誘導的突觸功能障礙方面顯示出效力[2]。"(1S,2R)-Alicapistat（9-21 nM）在不達到calpain抑制的IC 50的情況下具有CSF濃度，并在廣泛的人群研究中沒有顯示出劑量限制性毒性（DLTs）[3]。 |
| In vivo | (1S,2R)-Alicapistat (静脉注射或口服; 1-3 mg/kg) 在小鼠、大鼠和狗中显示出中等平均血浆清除率(CLp) (0.13-1.04 L/hr.kg)，而在猴子中较高 (1.98 L/hr.kg)。平均稳态分布体积(Vss)在小鼠、狗和猴中为中等(0.64-1.8 L/kg)，但在大鼠中更高 (3.4 L/kg)。血浆消除半衰期(t 1/2) 在狗中最短 (1.7小时)，其次是猴 (2.3小时)，小鼠和大鼠约为6.0小时。口服生物利用度(F)在小鼠、大鼠和狗中较高 (>80%)，而在猴中为中等 (14%) [2]。 |
| molecular weight | 433.5 |
| Molecular formula | C25H27N3O4 |
| CAS | 2221010-57-5 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| Solubility | DMSO: 45 mg/mL (103.81 mM), Sonication is recommended. |
| References | 1. Lon HK, et al. Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of Alicapistat, a Selective Inhibitor of Human Calpains 1 and 2 for the Treatment of Alzheimer Disease: An Overview of Phase 1 Studies. Clin Pharmacol Drug Dev. 2019 Apr. 8(3):290. 2. Jantos K, et al. Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability. Bioorg Med Chem Lett. 2019 Aug 1. 29(15):1968-1973. 3. Jastaniah A, Gaisina IN, Knopp RC, Thatcher GRJ. Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents. ChemMedChem. 2020 Dec 3. 15(23):2280-2285. |