Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile

Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonis...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-01, Vol.23 (1), p.90-95
Hauptverfasser:	Tamura, Yuusuke, Hayashi, Kyouhei, Omori, Naoki, Nishiura, Yuji, Watanabe, Kana, Tanaka, Nobuyuki, Fujioka, Masahiko, Kouyama, Naoki, Yukimasa, Akira, Tanaka, Yukari, Chiba, Takeshi, Tanioka, Hideki, Nambu, Hirohide, Yukioka, Hideo, Sato, Hiroki, Okuno, Takayuki
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral agonists Animals antagonists Anti-Obesity Agents - chemistry Anti-Obesity Agents - pharmacokinetics Anti-Obesity Agents - therapeutic use Benzimidazole Benzimidazoles - chemistry Benzimidazoles - pharmacokinetics Benzimidazoles - pharmacology Benzimidazoles - therapeutic use binding capacity Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - metabolism dose response food intake Gauche effect GPCR Half-Life in vivo studies Mice NPY Y5 receptor antagonist Obesity Obesity - drug therapy oral administration Rats Receptors, Neuropeptide Y - agonists Receptors, Neuropeptide Y - metabolism solubility Structure-Activity Relationship Sulfones - chemistry Sulfones - pharmacology Sulfones - therapeutic use weight gain Weight Gain - drug effects
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Zusammenfassung:	Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain. Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.11.005