A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice

doi:10.1073/pnas.0610173104

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	A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice
	Chen, Desu ; Liao, Jiayu ; Li, Na ; Zhou, Caihong ; Liu, Qing ; Wang, Guangxing ; Zhang, Rui ; Zhang, Song ; Lin, Lilin ; Chen, Kaixian
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2007-01-16
卷号	104 期号:3 页码:943-948
关键词	diabetes metabolism therapeutics
ISSN号	0027-8424
DOI	10.1073/pnas.0610173104
文献子类	Article
英文摘要	Peptidic mimics of the gut hormone glucagon-like peptide (GLIP) 1, exemplified by the recently approved drug exenatide, show promise as therapies for type 2 diabetes. Such "incretin mimetics" regulate glucose appearance in the plasma and can restore glucose-stimulated insulin secretion without excess risk of hypoglycemia. The need for injection, which may limit the use of peptidic GLP-1 receptor (GLP-1R) agonists, has driven largely unsuccessful efforts to find smaller molecules. The failure to identify orally effective agonists has instead promoted the indirect approach of inhibiting the GLP-1-degrading enzyme dipeptidyl peptidase IV. Here we report a nonpeptidic GLP-1R agonist with sufficient activity to evoke effects in whole animals, including antidiabetic efficacy in db/db mice. Two substituted cyclobutanes (S4P and Boc5) were developed after screening a compound library against a cell line stably cotransfected with GLP-1R and a cAMP-responsive reporter. Each bound to GLP-1R and increased intracellular cAMP. Agonist effects were blocked by the GLP-1R antagonist exendin(9-39). Boc5 amplified glucose-stimulated insulin secretion in isolated rat islets. Both i.p. and oral administration of Boc5 dose-dependently inhibited food intake in mice, an effect that could be blocked by pretreatment with exendin(9-39). Daily injections of BocS into db/db mice reduced HbA1c to nondiabetic values, an effect not observed in ad libitum-fed or pair-fed diabetic controls. Thus, Boc5 behaved as a full GLP-1 mimetic in vitro and in vivo. The chemical genus represented by Boc5 may prompt the exploration of orally available GLP-1R agonists with potential utility in diabetes and obesity.
WOS关键词	IMPROVED GLYCEMIC CONTROL ; BETA-CELL MASS ; INSULIN SENSITIVITY ; ZUCKER RATS ; GLUCOSE-CONCENTRATIONS ; EXENDIN-4 ; PANCREAS ; WEIGHT ; EXPRESSION ; OB/OB
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000243761100048
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273352]
专题	国家新药筛选中心
通讯作者	Wang, Ming-Wei
作者单位	1.Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab New Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Chen, Desu,Liao, Jiayu,Li, Na,et al. A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2007,104(3):943-948.
APA	Chen, Desu.,Liao, Jiayu.,Li, Na.,Zhou, Caihong.,Liu, Qing.,...&Wang, Ming-Wei.(2007).A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,104(3),943-948.
MLA	Chen, Desu,et al."A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 104.3(2007):943-948.