RESUMEN
A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode.
Asunto(s)
Piridinas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.
Asunto(s)
Hidrocarburos Fluorados/farmacología , Fenilpropionatos/farmacología , Piridinas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/química , Estructura Molecular , Fenilpropionatos/síntesis química , Fenilpropionatos/química , Relación Estructura-ActividadRESUMEN
A series of pyridine derivatives in the C-region of N-((6-trifluoromethyl-pyridin-3-yl)methyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. The SAR analysis indicated that 6-difluorochloromethyl pyridine derivatives were the best surrogates of the C-region for previous leads. Among them, compound 31 showed excellent antagonism to capsaicin as well as to multiple hTRPV1 activators. It demonstrated strong analgesic activity in the formalin test in mice with full efficacy and it blocked capsaicin-induced hypothermia in vivo.
Asunto(s)
Analgésicos/síntesis química , Bencenoacetamidas/síntesis química , Piridinas/química , Sulfonamidas/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Bencenoacetamidas/química , Bencenoacetamidas/farmacología , Bencenoacetamidas/uso terapéutico , Ratones , Estructura Molecular , Dolor/tratamiento farmacológico , Dimensión del Dolor , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/uso terapéuticoRESUMEN
A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (K(i(CAP)) = 0.2 nM; IC(50(pH)) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region.