| 產(chǎn)品描述： | ASP-9521是選擇性的、具有口服生物利用度的17beta-hydroxysteroid dehydrogenase type 5 (17β-HSD5)抑制劑 |
| 靶點(diǎn)： |
17β-HSD5;NADPH |
| 體外研究： |
In vitro, ASP9521 inhibited the conversion of androstenedione into testosterone by recombinant human and cynomolgus monkey AKR1C3 in a concentration-dependent manner, with IC50 values of 11 and 49 nmol/L, respectively. In contrast, ASP9521 did not inhibit the conversion by rat and mouse homologues (AKR1C1 and AKR1C6, respectively) up to a concentration of 10 μmol/L. ASP9521 showed moderately high selectivity (>100-fold) for human AKR1C3 (IC50: 120 nmol/L) over the human isoform AKR1C2 (IC50: >20,000 nmol/L) |
| 體內(nèi)研究： |
In murine models harbouring CWR22R xenograft tumours, single oral administration of ASP9521 suppressed AD-induced intratumoural testosterone production in a dose-dependent manner. This inhibitory effect was maintained for 24 h after single oral administration of ASP9521. Over this 24 h period, ASP9521 concentration rapidly decreased in plasma from 771.8 ng/mL (mean) to undetectable levels, while its intratumoural concentration reached its maximal level within 15 min after administration of ASP9521 and remained stable for 24 h. In nude mice bearing HEK293 tumours with or without AKR1C3 expression, after single oral administration of ASP9521, plasma concentrations of ASP9521 reached maximum values within 0.25 h (mean: 767.3 ng/mL and 648.2 ng/mL for HEK293 and HEK293-AKR1C3 cells, respectively), but decreased rapidly thereafter. Accumulation of ASP9521 in tumour tissue may depend on AKR1C3 expression. After single oral administration of 1 mg/kg ASP9521 to rats, dogs and monkeys, the drug was rapidly absorbed. The bioavailability values were 35 %, 78 %, and 58 %, respectively. After iv administration of ASP9521 to rats, dogs and monkeys, plasma concentrations of the drug declined with t1/2 values of 0.2, 1.7 and 5.8 h, respectively |
| 細(xì)胞實(shí)驗(yàn)： |
Cell lines: LNCaP-AKR1C3 cells stably expressing human AKR1C3 Concentrations: 0.3-100 nmol/L Incubation Time: 24 h or 6 days Method: LNCaP-AKR1C3 cells stably expressing human AKR1C3 were seeded in 96-well plates at 1x 104 cells/100 μL/well in RPMI-1640 medium supplemented with heat-inactivated charcoal-dextran-stripped FBS (1 % for the PSA expression assay and T measurement and 5 % for the cell proliferation assay). After 24 h incubation, AD was added to each well with or without ASP9521 (0.3-100 nmol/L). The cell culture media were collected 24 h after administration of AD to measure T concentration and 6 days after administration of AD to measure either PSA levels or cell proliferation. |
| 動(dòng)物實(shí)驗(yàn)： |
Animal Models: Male Balb/c athymic nude mice (4-6 weeks old) with CWR22R tumours Dosages: 1, 3 or 10 mg/kg Administration: oral administration |
| 參考文獻(xiàn)： |
1. Kikuchi A, et al. In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3). Invest New Drugs. 2014, 32(5):860-70. |
| 溶解性： |
Soluble in DMSO、Ethanol |
| 保存條件： |
-20℃ |
| 配置溶液濃度參考： |
|
1mg |
5mg |
10mg |
| 1 mM |
3.026 ml |
15.132 ml |
30.264 ml |
| 5 mM |
0.605 ml |
3.026 ml |
6.053 ml |
| 10 mM |
0.303 ml |
1.513 ml |
3.026 ml |
| 50 mM |
0.061 ml |
0.303 ml |
0.605 ml |
|
| 注意： |
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