A preliminary study of the metabolic stability of a series of benzoxazinone derivatives as potent neuropeptide Y5 antagonists

Dordal, Alberto; Lipkin, M. A.; Macritchie, Jackie; Más, Josep; Port, Adriana; Rose, Sally; Salgado, Leonardo; Savić, Vladimir; Schmidt, Wolfgang; Serafini, Maria Teresa; Spearing, William; Torrens, Antoni; Yeste, Sandra

doi:10.1016/j.bmcl.2005.05.103

Cited by 3 publications

(1 citation statement)

References 14 publications

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“…SAR studies identified a potent 1 nM guanidine (24), which was orally active and brain penetrant [115]. Benzoxazinone derivatives have been optimized to yield moderately potent compounds, which are selective over Y1, Y2 and 50 other targets [116]. A 50 nM Y5 antagonist (25), inhibited food intake in fasted rats [117].…”

Section: Y5 Antagonistsmentioning

confidence: 99%

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

MacNeil¹

2007

CTMC

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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.

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