Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor
Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor
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DOI：
10.1128/aac.02719-13
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发表时间：
2014-06-01
影响因子：
4.9
通讯作者：
Yoakim, Christiane
中科院分区：
文献类型：
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作者：
Fenwick, Craig;Amad, Ma'an;Yoakim, Christiane
BI 224436是一种具有有效抗病毒活性的HIV-1整合酶抑制剂，其作用机制与整合酶链转移抑制剂（INSTI）不同。该3-喹啉乙酸衍生物系列使用酶整合酶长末端重复（LTR）DNA 3 '-加工测定法鉴定。药物化学、平行合成和结构指导药物设计的组合导致BI 224436被确定为临床前特征分析的候选药物。其抗病毒50%有效浓度（EC（50）s）为90 μ M。在存在50%人血清的情况下，BI 224436的抗病毒效力也有较低的降低，接近2.1倍，并且由于剂量-反应曲线斜率陡峭，显示血清偏移的EC 95值范围为22 - 75 nM。在存在针对A128 T、A128 N或L102 F原发性抗性取代选择的抑制剂的情况下病毒的传代，所有这些都映射到整合酶的催化核心上的保守变构口袋。BI 224436还保留了对编码RNAi耐药置换N155 S、Q148 H和E92 Q的重组病毒的完全抗病毒活性。在细胞抗病毒试验中进行的联合用药研究中，BI 224436与大多数获批的抗逆转录病毒药物（包括INSTI）联合使用时显示出累加效应。BI 224436具有药物样体外吸收、分布、代谢和排泄（ADME）特性，包括Caco-2细胞渗透性、溶解度和低细胞色素P450抑制。其在大鼠（清除率占肝流量的百分比[CL]，0.7%;生物利用度[F]，54%）、猴（CL，23%; F，82%）和犬（CL，8%; F，81%）中表现出优异的药代动力学特征。基于出色的生物学和药代动力学特征，BI 224436进入I期临床试验。
BI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3'-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC(50)s) of 90 mu M. BI 224436 also has a low, similar to 2.1-fold decrease in antiviral potency in the presence of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits serum-shifted EC95 values ranging between 22 and 75 nM. Passage of virus in the presence of inhibitor selected for either A128T, A128N, or L102F primary resistance substitutions, all mapping to a conserved allosteric pocket on the catalytic core of integrase. BI 224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials.