A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice.
Peptidic mimics of the gut hormone glucagon-like peptide (GLP) 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 Boc5 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.
Chen
Desu
D
National Center for Drug Screening, 189 Guo Shou Jing Road, Zhangjiang High-Tech Park, Pudong, Shanghai 201203, China.
Liao
Jiayu
J
Li
Na
N
Zhou
Caihong
C
Liu
Qing
Q
Wang
Guangxing
G
Zhang
Rui
R
Zhang
Song
S
Lin
Lilin
L
Chen
Kaixian
K
Xie
Xin
X
Nan
Fajun
F
Young
Andrew A
AA
Wang
Ming-Wei
MW
D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D002908:Chronic Disease / Q000188:drug therapy; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010455:Peptides / Q000627:therapeutic use; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism
C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon