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

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 microM 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.

• Authors: 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
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 52 Issue 2 Pg. 655-65 (Feb 2008) ISSN: 0066-4804 [Print] United States
• PMID: 18056282 (Publication Type: Journal Article)

Chemical References

• Anti-HIV Agents
• GS-9131
• Organophosphonates
• Prodrugs
• Reverse Transcriptase Inhibitors
• Guanosine
• GS-9148
• Adenine

Topics

• Adenine (analogs & derivatives, chemistry, metabolism, pharmacology)
• Animals
• Anti-HIV Agents (chemistry, metabolism, pharmacology)
• CD4-Positive T-Lymphocytes (immunology, metabolism, virology)
• Cell Line
• Dogs
• Drug Design
• Drug Resistance, Viral
• Guanosine (analogs & derivatives, chemistry, metabolism, pharmacology)
• HIV-1 (drug effects)
• Humans
• Leukocytes, Mononuclear (immunology, metabolism, virology)
• Macrophages (immunology, metabolism, virology)
• Male
• Microbial Sensitivity Tests
• Organophosphonates (chemistry)
• Prodrugs (chemistry, metabolism, pharmacology)
• Reverse Transcriptase Inhibitors (chemistry, metabolism, pharmacology)