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.

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. Research Abstract Details 

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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. Abstract Text:

Tomas Cihlar,Adrian S Ray,Constantine G Boojamra,Lijun Zhang,Hon Hui,Genevieve Laflamme,Jennifer E Vela,Deborah Grant,James Chen,Florence Myrick,Kirsten L White,Ying Gao,Kuei-Ying Lin,Janet L Douglas,Neil T Parkin,Anne Carey,Rowchanak Pakdaman,Richard L Mackman,Tomas Cihlar,Adrian S Ray,Constantine G Boojamra,Lijun Zhang,Hon Hui,Genevieve Laflamme,Jennifer E Vela,Deborah Grant,James Chen,Florence Myrick,Kirsten L White,Ying Gao,Kuei-Ying Lin,Janet L Douglas,Neil T Parkin,Anne Carey,Rowchanak Pakdaman,Richard L Mackman,

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 1 (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. Gao, 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 muM) 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 muM 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.

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. Publishing Authors By Initials

T Cihlar,AS Ray,CG Boojamra,L Zhang,H Hui,G Laflamme,JE Vela,D Grant,J Chen,F Myrick,KL White,Y Gao,KY Lin,JL Douglas,NT Parkin,A Carey,R Pakdaman,RL Mackman,T Cihlar,AS Ray,CG Boojamra,L Zhang,H Hui,G Laflamme,JE Vela,D Grant,J Chen,F Myrick,KL White,Y Gao,KY Lin,JL Douglas,NT Parkin,A Carey,R Pakdaman,RL Mackman,

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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. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Antimicrobial agents and chemotherapy

VOLUME: 52

Page Numbers: 655-65

Journal Abbreviation: Antimicrob. Agents Chemother.

ISSN: 0066-4804

DAY: 3

MONTH: 12

YEAR: 2007

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. Information

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LANGUAGE: eng

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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. Keywords Mesh Terms:

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Grant and Affiliation Information for 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.

AFFILIATION: Gilead Sciences, 333 Lakeside Dr., Foster City, CA 94404. tomas.cihlar@gilead.com.

Country: United States

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MEDLINETA: Antimicrob Agents Chemother

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