OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

doi:10.1038/aps.2016.27

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	OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition
	Ma, Shan-yao; Ning, Meng-meng; Zou, Qing-an; Feng, Ying; Ye, Yang-liang; Shen, Jian-hua; Leng, Ying
刊名	ACTA PHARMACOLOGICA SINICA
	2016-10
卷号	37 期号:10 页码:1359-1369
关键词	OL3 MN6 linagliptin TGR5 agonist DPP4 inhibitor GLP-1 low-absorbed gallbladder filling type 2 diabetes mellitus
ISSN号	1671-4083
DOI	10.1038/aps.2016.27
文献子类	Article
英文摘要	Aim: TGR5 agonists stimulate intestinal glucagon-like peptide-1 (GLP-1) release, but systemic exposure causes unwanted side effects, such as gallbladder filling. In the present study, linagliptin, a DPP-4 inhibitor with a large molecular weight and polarity, and MN6, a previously described TGR5 agonist, were linked to produce OL3, a novel low-absorbed TGR5 agonist with reduced side-effects and dual function in lowering blood glucose by activation of TGR5 and inhibition of DPP-4. Methods: TGR5 activation was assayed in HEK293 cells stably expressing human or mouse TGR5 and a CRE-driven luciferase gene. DPP-4 inhibition was assessed based on the rate of hydrolysis of a surrogate substrate. GLP-1 secretion was measured in human enteroendocrine NCI-H716 cells. OL3 permeability was tested in Caco-2 cells. Acute glucose-lowering effects of OL3 were evaluated in ICR and diabetic ob/ob mice. Results: OL3 activated human and mouse TGR5 with an EC50 of 86.24 and 17.36 nmol/L, respectively, and stimulated GLP-1 secretion in human enteroendocrine NCI-H716 cells (3-30 mu mol/L). OL3 inhibited human and mouse DPP-4 with IC50 values of 18.44 and 69.98 mu mol/L, respectively. Low permeability of OL3 was observed in Caco-2 cells. In ICR mice treated orally with OL3 (150 mg/kg), the serum OL3 concentration was 101.10 ng/mL at 1 h, and decreased to 13.38 ng/mL at 5.5 h post dose, confirming the low absorption of OL3 in vivo. In ICR mice and ob/ob mice, oral administration of OL3 significantly lowered the blood glucose levels, which was a synergic effect of activating TGR5 that stimulated GLP-1 secretion in the intestine and inhibiting DPP-4 that cleaved GLP-1 in the plasma. In ICR mice, oral administration of OL3 did not cause gallbladder filling. Conclusion: OL3 is a low-absorbed TGR5 agonist that lowers blood glucose without inducing gallbladder filling. This study presents a new strategy in the development of potent TGR5 agonists in treating type 2 diabetes, which target to the intestine to avoid systemic side effects.
资助项目	National Natural Science Foundation of China[81473093] ; State Key Laboratory of Drug Research[SIMM1403ZZ-03] ; Shanghai Institute of Materia Medica[CASIMM0120152030]
WOS关键词	BILE-ACID RECEPTOR ; PEPTIDE-1 SECRETION ; MEMBRANE-RECEPTOR ; MICE ; DISORDERS ; TARGET ; POTENT ; IDENTIFICATION ; STIMULATION ; DERIVATIVES
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000385634300009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275878]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室药理学第一研究室
通讯作者	Shen, Jian-hua; Leng, Ying
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Ma, Shan-yao,Ning, Meng-meng,Zou, Qing-an,et al. OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition[J]. ACTA PHARMACOLOGICA SINICA,2016,37(10):1359-1369.
APA	Ma, Shan-yao.,Ning, Meng-meng.,Zou, Qing-an.,Feng, Ying.,Ye, Yang-liang.,...&Leng, Ying.(2016).OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition.ACTA PHARMACOLOGICA SINICA,37(10),1359-1369.
MLA	Ma, Shan-yao,et al."OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition".ACTA PHARMACOLOGICA SINICA 37.10(2016):1359-1369.