NPY Y1 and Y5 Receptor Selective Antagonists as Anti-Obesity Drugs

Abstract

A combination of pharmacological and genetic studies in mice confirmed that the Y1 and Y5 receptors mediate the potent orexigenic actions of exogenous NPY. Although the physiological role of NPY in causing obesity is less clear, potent and selective antagonists of both Y1 and Y5 have been developed. Some of the NPY antagonists have suitable pharmacokinetic (PK) properties that allowed them to be evaluated in various rodent models of obesity. Several different Y1 and Y5 antagonists cause weight loss in rodent models, though confirmation that these effects are mechanism based has been limited. One Y5 antagonist, MK-0557 was evaluated in a 1-yr clinical trial and found to cause modest weight loss. Optimal NPY antagonist therapeutics for obesity may require blockade of both the Y1 and Y5 receptors.

Synthesis, characterization, and monkey positron emission tomography (PET) studies of [18F]Y1-973, a PET tracer for the neuropeptide Y Y1 receptor

“…The Y2 and Y4 receptor subtypes are proposed to inhibit appetite, while the Y1 and Y5 subtypes have been implicated in stimulating appetite. Therefore, inhibition of NPY Y1 or NPY Y5 has been pursued as a potential therapy for obesity (MacNeil, 2007).…”

G protein-coupled receptors in energy homeostasis

“…A recent study has shown that leptin could stimulate the NPY neuron activity in the hypothalamus in diet-induced obese mice, indicating the role of NPY in leptin-mediated appetite control [63]. Several Y receptor antagonists targeting Y1, Y2, Y4 and Y5 were shown to cause weight loss or protection against diet-induced obesity in rodent models [64,65]. Furthermore, ablation of both Y2 and Y4 receptors in ob/ob mice attenuated the hyperphagia-caused obesity [66].…”

In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y2 receptor

“…However, the magnitude of induced-weight loss by MK-0557 (spiro[cyclohexane-1,3′(1′H)-furo[3,4-c]pyridine]-4-carboxamide,N-[1-(2-fluorophenyl)-1H-pyrazol-3-yl]-1′-oxo-, trans-), one of these selective Y 5 antagonists, was not clinically meaningful despite demonstrated high levels of Y 5 receptor occupancy (Erondu et al 2006). Potent and selective antagonists of the Y 1 receptor from various chemical classes have also been developed for the treatment of obesity (MacNeil 2007). In contrast to Y 1 and Y 5 receptor subtypes, for which many selective antagonists from various chemical classes are available, discovering Y 2 receptor antagonists has proven challenging.…”