RESUMEN
The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.
Asunto(s)
Analgésicos/síntesis química , Naftiridinas/síntesis química , Pirazinas/síntesis química , Piridinas/síntesis química , Pirimidinas/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Células COS , Capsaicina/farmacología , Chlorocebus aethiops , Calor , Humanos , Hiperalgesia/tratamiento farmacológico , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Microsomas Hepáticos , Naftiridinas/química , Naftiridinas/farmacología , Dolor/tratamiento farmacológico , Pirazinas/química , Pirazinas/farmacología , Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/farmacología , Quinolinas/síntesis química , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Canales Catiónicos TRPV/agonistasRESUMEN
A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.
Asunto(s)
Aminoquinolinas/farmacología , Química Farmacéutica/métodos , Canales Catiónicos TRPV/antagonistas & inhibidores , Aminoquinolinas/química , Animales , Perros , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/química , Inflamación/tratamiento farmacológico , Cinética , Modelos Químicos , Conformación Molecular , Dolor/tratamiento farmacológico , Preparaciones Farmacéuticas/química , Ratas , Canales Catiónicos TRPV/químicaRESUMEN
Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series.