ABT-538 IS A POTENT INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE AND HAS HIGH ORAL BIOAVAILABILITY IN HUMANS
ABT-538 IS A POTENT INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE AND HAS HIGH ORAL BIOAVAILABILITY IN HUMANS
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DOI：
10.1073/pnas.92.7.2484
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发表时间：
1995-03-28
影响因子：
11.1
通讯作者：
NORBECK, DW
中科院分区：
文献类型：
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作者：
KEMPF, DJ;MARSH, KC;NORBECK, DW
对一系列基于乙酰基的人类免疫缺陷病毒（HIV）蛋白酶抑制剂的抗病毒活性、口服药代动力学和肝脏代谢的结构基础的检查导致ABT-538的发现，ABT-538是用于获得性免疫缺陷综合征（AIDS）的治疗干预的有希望的实验药物，ABT-538对HIV-1 [50%有效浓度（EC（50））= 0.022-0.13 μ M]和HIV-2（EC（50）= 0.16 μ M）的实验室和临床菌株显示出有效的体外活性。单次口服10 mg/kg剂量后，大鼠、犬和猴的血浆浓度超过体外抗病毒EC（50）> 12 h。在人体试验中，单次400 mg剂量的ABT-538显示出延长的吸收曲线，并达到超过5 μ g/ml的峰值血浆浓度。这些发现表明，HIV蛋白酶的拟肽抑制剂可在人体中实现高口服生物利用度。
Examination of the structural basis for antiviral activity, oral pharmacokinetics, and hepatic metabolism among a series of symmetry-based inhibitors of the human immunodeficiency virus (HIV) protease led to the discovery of ABT-538, a promising experimental drug for the therapeutic intervention in acquired immunodeficiency syndrome (AIDS), ABT-538 exhibited potent in vitro activity against laboratory and clinical strains of HIV-1 [50% effective concentration (EC(50)) = 0.022-0.13 mu M] and HIV-2 (EC(50) = 0.16 mu M). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC(50) for > 12 h. In human trials, a single 400-mg dose of ABT-538 displayed a prolonged absorption profile and achieved a peak plasma concentration in excess of 5 mu g/ml, These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease.