RESUMEN
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 (3mg/kg) in Beagle dogs, high levels (>9.0microM) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/farmacología , Guanosina/análogos & derivados , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/farmacología , Adenina/síntesis química , Adenina/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Linfocitos T CD4-Positivos/efectos de los fármacos , Perros , Diseño de Fármacos , Farmacorresistencia Viral/efectos de los fármacos , Estabilidad de Medicamentos , Guanosina/farmacología , Nucleósidos/farmacología , Organofosfonatos/farmacología , Profármacos/metabolismo , Profármacos/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Células Tumorales CultivadasRESUMEN
A diphosphate of a novel cyclopentyl based nucleoside phosphonate with potent inhibition of HIV reverse transcriptase (RT) (20, IC(50)=0.13 microM) has been discovered. In cell culture the parent phosphonate diacid 9 demonstrated antiviral activity EC(50)=16 microM, within two-fold of GS-9148, a prodrug of which is currently under clinical investigation, and within 5-fold of tenofovir (PMPA). In vitro cellular metabolism studies using 9 confirmed that the active diphosphate metabolite is produced albeit at a lower efficiency relative to GS-9148.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Nucleósidos/síntesis química , Organofosfonatos/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Línea Celular Tumoral , Diseño de Fármacos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/química , Humanos , Modelos Moleculares , Estructura Molecular , Nucleósidos/química , Nucleósidos/farmacología , Organofosfonatos/química , Organofosfonatos/farmacología , Profármacos/síntesis química , Profármacos/farmacocinética , Profármacos/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Relación Estructura-ActividadRESUMEN
GS-9148 (2'-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC(50)=12 microM). Unlike many clinical RT inhibitors, relevant reverse transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2'-Fd4AP that is similar to wild-type virus. The 2'-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Flúor/química , Guanosina/análogos & derivados , Guanosina/síntesis química , Guanosina/farmacología , Nucleósidos/síntesis química , Nucleósidos/farmacología , Organofosfonatos/síntesis química , Organofosfonatos/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/química , ADN Mitocondrial/efectos de los fármacos , Guanosina/química , Transcriptasa Inversa del VIH/genética , Humanos , Estructura Molecular , Nucleósidos/química , Organofosfonatos/química , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-Actividad , Zidovudina/farmacologíaRESUMEN
A series of nucleoside phosphonate reverse transcriptase (RT) inhibitors have been synthesized and their anti-HIV activity and resistance profiles evaluated. The most potent analog [5-(6-amino-purin-9-yl)-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid (d4AP) demonstrated a HIV EC(50)=2.1 microM, and the most favorable resistance profile against HIV-1 variants with K65R, M184V or multiple thymidine analog mutations in RT.