RESUMEN
A series of small molecules with a piperidinyl core were synthesized and tested for binding affinity (IC50) at human Neuropeptide Y Y2 receptor. Various amide related analogs (ureas, reversed amides, and sulfonamides) were evaluated. Several potent and selective NPY Y2 antagonists were identified.
Asunto(s)
Amidas/química , Receptores de Neuropéptido Y/antagonistas & inhibidores , Amidas/síntesis química , Amidas/metabolismo , Animales , Evaluación Preclínica de Medicamentos , Humanos , Microsomas/metabolismo , Unión Proteica , Ratas , Receptores de Neuropéptido Y/metabolismo , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/metabolismo , Urea/síntesis química , Urea/química , Urea/metabolismoRESUMEN
A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC(50)) at the human Neuropeptide Y Y(2) receptor (NPY Y(2)). Six of the 23 analogs tested possessed an NPY Y(2) IC(50) ≤ 15 nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing as a racemic mixture. As such a synthetic route to the desired enantiomer was designed starting from commercially available (S)-(+)-mandelic acid.