RESUMEN
Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.
Asunto(s)
Fármacos Anti-VIH/química , Antagonistas de los Receptores CCR5 , Ciclohexanos/química , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Triazoles/química , Fármacos Anti-VIH/uso terapéutico , Ciclohexanos/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Maraviroc , Receptores CCR5/metabolismo , Triazoles/uso terapéuticoAsunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Antagonistas de los Receptores CCR5 , Ciclobutanos/química , Ciclobutanos/farmacología , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/síntesis química , Bencimidazoles/síntesis química , Ciclobutanos/síntesis química , Humanos , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
The discovery of maraviroc 17 is described with particular reference to the generation of high selectivity over affinity for the HERG potassium channel. This was achieved through the use of a high throughput binding assay for the HERG channel that is known to show an excellent correlation with functional effects.
Asunto(s)
Antagonistas de los Receptores CCR5 , Canales de Potasio Éter-A-Go-Go/metabolismo , Antivirales/química , Antivirales/farmacología , Línea Celular , Quimiocina CCL4 , VIH/efectos de los fármacos , Humanos , Proteínas Inflamatorias de Macrófagos/antagonistas & inhibidores , Proteínas Inflamatorias de Macrófagos/metabolismo , Modelos Moleculares , Estructura Molecular , Receptores CCR5/metabolismo , Relación Estructura-ActividadRESUMEN
The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.
Asunto(s)
Fármacos Anti-VIH/química , Antagonistas de los Receptores CCR5 , Tropanos/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Inhibidores del Citocromo P-450 CYP2D6 , VIH-1/efectos de los fármacos , Humanos , Modelos Moleculares , Piperidinas/química , Receptores CCR5/metabolismo , Relación Estructura-Actividad , Tropanos/síntesis química , Tropanos/farmacologíaRESUMEN
Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 microM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS.