Orally active ghrelin receptor inverse agonists and their actions on a rat obesity model

被引：14

作者：

Takahashi, Bitoku ^{[1
]}

Funami, Hideaki ^{[1
]}

Iwaki, Takehiko ^{[1
]}

Maruoka, Hiroshi ^{[1
]}

Shibata, Makoto ^{[1
]}

Koyama, Makoto ^{[1
]}

Nagahira, Asako ^{[1
]}

Kamiide, Yoshiyuki ^{[1
]}

Kanki, Satomi ^{[1
]}

Igawa, Yoshiyuki ^{[1
]}

Muto, Tsuyoshi ^{[1
]}

机构：

[1] Asubio Pharma Co Ltd, Chuo Ku, Kobe, Hyogo 6500047, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 15期

关键词：

GhrelinR; Inverse agonist; 2-Aminoalkyl nicotinamide; Obesity; GROWTH-HORMONE SECRETION; IDENTIFICATION; POTENT; PEPTIDE;

D O I：

10.1016/j.bmc.2015.05.047

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：4792 / 4803

页数：12

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