RESUMEN
Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Unión Competitiva , Línea Celular Tumoral , Quimiotaxis de Leucocito/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Indoles/farmacología , Mastocitos/efectos de los fármacos , Ratones , Piperazinas/farmacocinética , Ratas , Receptores Histamínicos , Receptores Histamínicos H4RESUMEN
The Orphan Drug Act has been successful in providing incentives to find cures for orphan diseases. However, many orphan diseases are still without cure. Therefore, the 114th Congress has introduced the 21st Century Cures Act and the Orphan Product Extension Now Accelerating Cures and Treatment Act of 2015 to further provide incentives to innovators to repurpose existing drugs for treatment of these orphan diseases. However, these bills are currently pending and their incentives might not go far enough.
RESUMEN
Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.