RESUMEN
A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.
Asunto(s)
Amidas/química , Antagonistas de los Receptores Histamínicos H3/química , Receptores Histamínicos H3/química , Urea/química , Amidas/metabolismo , Amidas/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Células HEK293 , Antagonistas de los Receptores Histamínicos H3/metabolismo , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Humanos , Macaca mulatta , Obesidad/tratamiento farmacológico , Unión Proteica , Ratas , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Relación Estructura-Actividad , Urea/metabolismo , Urea/uso terapéuticoRESUMEN
A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition in diet-induced obese (DIO) mice. Compound 2q represents a novel H3R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.