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A series of new pyridine hydrazide derivatives with high and selective antagonist activity at the human neuropeptide Y Y5 receptor were developed. Introduction of electron-withdrawing groups into the arylsulfonamide rest, together with the 3-pyridyl analogue in the hydrazide moiety, led to a significant improvement of potency and solubility, affording trans-N-(4-[N'-(pyridine-3-carbonyl)hydrazino-carbonyl]cyclohexylmethyl)-2,4-dichloro-benzenesulfonamide (14), which binds to the hY5 receptor with an IC50 value of 7.44 nmol/L.

NPY is the most potent orexigenic agent known to man, with NPY Y1 and NPY Y5 being the receptor subtypes that are most likely responsible for centrally-mediated NPY-induced feeding responses. Based on the aforementioned, novel hydrazide derivatives were prepared for the purpose of searching new NPY Y5 receptor antagonists. Many of the compounds exhibited nanomolar binding affinity for this receptor, affording trans-N-(4-[N'-(3,4-dichlorophenyl)hydrazinocarbonyl]cyclohexylmethyl)-4-fluorobenzenesulfonamide, which showed the best activity (IC(50)=0.43nM).