Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131

被引：80

作者：

Cihlar, Tomas ^{[1
]}

Ray, Adrian S. ^{[1
]}

Boojamra, Constantine G. ^{[1
]}

Zhang, Lijun ^{[1
]}

Hui, Hon ^{[1
]}

Laflamme, Genevieve ^{[1
]}

Vela, Jennifer E. ^{[1
]}

Grant, Deborah ^{[1
]}

Chen, James ^{[1
]}

Myrick, Florence ^{[2
]}

White, Kirsten L. ^{[1
]}

Gao, Ying ^{[1
]}

Lin, Kuei-Ying ^{[1
]}

Douglas, Janet L. ^{[1
]}

Parkin, Neil T. ^{[3
]}

Carey, Anne ^{[1
]}

Pakdaman, Rowchanak ^{[1
]}

Mackman, Richard L. ^{[1
]}

机构：

[1] Gilead Sci Inc, Foster City, CA 94404 USA

[2] Gilead Sci Inc, Durham, NC USA

[3] Monogram Biosci, San Francisco, CA USA

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2008年 / 52卷 / 02期

关键词：

D O I：

10.1128/AAC.01215-07

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] is a novel ribose-modified human immunodeficiency virus type I (HIV-1) nucleotide reverse transcriptase (RT) inhibitor (NRTI) selected from a series of nucleoside phosphonate analogs for its favorable in vitro biological properties including (i) a low potential for mitochondrial toxicity, (ii) a minimal cytotoxicity in renal proximal tubule cells and other cell types, (iii) synergy in combination with other antiretrovirals, and (iv) a unique resistance profile against multiple NRTI-resistant HIV-1 strains. Notably, antiviral resistance analysis indicated that neither the K65R, L74V, or M184V RT mutation nor their combinations had any effect on the antiretroviral activity of GS-9148. Viruses carrying four or more thymidine analog mutations showed a substantially smaller change in GS-9148 activity relative to that observed with most marketed NRTIs. GS-9131, an ethylalaninyl phosphonoamidate prodrug designed to maximize the intracellular delivery of GS-9148, is a potent inhibitor of multiple subtypes of HIV-1 clinical isolates, with a mean 50% effective concentration of 37 nM. Inside cells, GS-9131 is readily hydrolyzed to GS-9148, which is further phosphorylated to its active diphosphate metabolite (A. S. Ray, J. E. Vela, C. G. Boojamra, L. Zhang, H. Hui, C. Callebaut, K. Stray, K.-Y. Lin, Y. Gan, R. L. Mackman, and T. Cihlar, Antimicrob. Agents Chemother. 52:648-654, 2008). GS-9148 diphosphate acts as a competitive inhibitor of RT with respect to dATP (K-i = 0.8 mu M) and exhibits low inhibitory potency against host polymerases including DNA polymerase gamma. Oral administration of GS-9131 to beagle dogs at a dose of 3 mg/kg of body weight resulted in high and persistent levels of GS-9148 diphosphate in peripheral blood mononuclear cells (with a maximum intracellular concentration of >9 mu M and a half-life of >24 h). This favorable preclinical profile makes GS-9131 an attractive clinical development candidate for the treatment of patients infected with NRTI-resistant HIV.

引用

页码：655 / 665

页数：11

共 51 条

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