RESUMEN
A structure-activity relationship study of the lead piperazinylcarbonylpiperidine compound 3 resulted in the identification of 4-benzimidazolyl-piperidinylcarbonyl-piperidine 6h as a histamine-3 (H(3)) receptor antagonist. Additional optimization of 6h led to the identification of compounds 11i-k with K(i) Asunto(s)
Antagonistas de los Receptores Histamínicos H3/síntesis química
, Antagonistas de los Receptores Histamínicos H3/farmacología
, Piperidinas/síntesis química
, Piperidinas/farmacología
, Relación Estructura-Actividad
RESUMEN
A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/farmacología , Piperidinas/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Cobayas , Haplorrinos , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Ratas , Relación Estructura-Actividad , Distribución TisularRESUMEN
A novel non-imidazole fluorene oxime 1a has been identified as a histamine H(3) inhibitor, and its structure-activity relationship has been evaluated.
Asunto(s)
Fluorenos/síntesis química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Receptores Histamínicos H3/efectos de los fármacos , Fluorenos/química , Fluorenos/farmacología , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Relación Estructura-ActividadRESUMEN
The structural modification of the benzylic ether region of oxime 1 has resulted in the identification of several novel aryl amides as selective or dual NK(1)/NK(2) antagonists.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Oximas/síntesis química , Oximas/farmacología , Receptores de Neuroquinina-2/antagonistas & inhibidores , Oximas/química , Relación Estructura-ActividadRESUMEN
A novel series of histamine H(3) receptor antagonists, based on the 4-benzyl-(1H-imidazole-4-yl) template, incorporating urea and carbamate linkers has been prepared. Compound 3j is a selective H(3) antagonist and demonstrates excellent oral plasma levels in the rat and monkey.