RESUMEN
Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.
RESUMEN
A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective delta-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure-activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series.
Asunto(s)
4-Aminopiridina/análogos & derivados , Química Farmacéutica/métodos , Canales de Potasio Éter-A-Go-Go/química , Receptores Opioides delta/agonistas , 4-Aminopiridina/síntesis química , 4-Aminopiridina/farmacología , Analgésicos Opioides/farmacología , Animales , Línea Celular , Técnicas Químicas Combinatorias , Diseño de Fármacos , Canal de Potasio ERG1 , Electromiografía/métodos , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Modelos Químicos , Ratas , Receptores Opioides delta/química , Relación Estructura-ActividadRESUMEN
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.