Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148
Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148
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DOI：
10.1016/j.bmc.2010.03.041
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发表时间：
2010-05-15
影响因子：
3.5
通讯作者：
Cihlar, Tomas
中科院分区：
文献类型：
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作者：
Mackman, Richard L.;Ray, Adrian S.;Cihlar, Tomas
GS-9148[（5-（6-氨基嘌呤-9-酰基）-4-氟-2,5-二氢呋喃-2-酰基甲基）膦酸]4是一种新型磷酸核苷类HIV-1逆转录酶（RT）抑制剂，对N(t)RTI耐药突变具有独特的抗性谱。为了将4及其活性磷酸化代谢物15有效地递送到靶细胞，设计了一系列酰胺类前药作为组织蛋白酶a的底物，组织蛋白酶a是一种在外周血单核细胞（PBMCs）中高度表达的细胞内溶酶体羧肽酶。乙基丙氨酸酰膦酰胺前药5 （GS-9131）表现出良好的组织蛋白酶A底物特性，以及良好的体外肠和肝稳定性。Beagle犬口服给药（3mg /kg）后，在pbmc中观察到高水平（>9.0 μ M）的活性代谢物15，验证了药前设计过程，并导致5被提名为临床候选药物。(C) 2010 Elsevier Ltd.版权所有。
GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] 4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver 4 and its active phosphorylated metabolite 15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug 5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3 mg/kg) in Beagle dogs, high levels (>9.0 mu M) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate. (C) 2010 Elsevier Ltd. All rights reserved.