Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Apr 21;8(5):560-565.
doi: 10.1021/acsmedchemlett.7b00116. eCollection 2017 May 11.

Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes

Xuqing Zhang  1 , Mark Wall  1 , Zhihua Sui  1 , Jack Kauffman  1 , Cuifen Hou  1 , Cailin Chen  1 , Fuyong Du  1 , Thomas Kirchner  1 , Yin Liang  1 , Dana L Johnson  1 , William V Murray  1 , Keith Demarest  1
Affiliations

Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes

Xuqing Zhang et al. ACS Med Chem Lett. .

Abstract

We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure-activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGR5. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGR5 (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)0-120 min in oral glucose tolerance tests (OGTT).

Keywords: OGTT; TGR5; tetrahydrobenzimidazoles; type 2 diabetes.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Tetrahydrobenzimidazoles via ring restriction.
Figure 2
Figure 2
Study 1: OGTT studies of 54–57 and 59–61 in C57/BL6 mice. Compound (30 mg/kg in 20% HPBCD) or 20% HPBCD (vehicle control) was orally administered at −30 min of OGTT followed by oral glucose challenge at 2.0 g/kg at 0 min. Blood glucose was measured at −30, 0, 30, 60, and 120 min after administration (n = 8 animals/group).
Figure 3
Figure 3
Study 2: OGTT studies of 51, 53 and 58 in C57 BL/6 mice. Compound (30 mg/kg in 20% HPBCD) or 20% HPBCD (vehicle control) was orally administered at −30 min of OGTT followed by oral glucose challenge at 2.0 g/kg at 0 min. Blood glucose was measured at −30, 0, 30, 60, and 120 min after administration (n = 8 animals/group).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Tiwari A.; Maiti P. TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders. Drug Discovery Today 2009, 14, 523–530. 10.1016/j.drudis.2009.02.005. - DOI - PubMed
    1. Maruyama T.; Miyamoto Y.; Nakamura T.; Tamai Y.; Okada H.; Sugiyama E.; Nakamura T.; Itadani H.; Tanaka K. Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 2002, 298, 714–719. 10.1016/S0006-291X(02)02550-0. - DOI - PubMed
    1. Kawamata Y.; Fujii R.; Hosoya M.; Harada M.; Yoshida H.; Miwa M.; Fukusumi S.; Habata Y.; Itoh T.; Shintani Y.; Hinuma S.; Fujisawa Y.; Fujino M. A. G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 2003, 278, 9435–9440. 10.1074/jbc.M209706200. - DOI - PubMed
    1. Thomas C.; Pellicciari R.; Pruzanski M.; Auwerx J.; Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discovery 2008, 7, 678–693. 10.1038/nrd2619. - DOI - PubMed
    1. Watanabe M.; Houten S. M.; Mataki C.; Christoffolete M. A.; Kim B. W.; Sato H.; Messaddeq N.; Harney J. W.; Ezaki O.; Kodama T.; Schoonjans K.; Bianco A. C.; Auwerx J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006, 439, 484–489. 10.1038/nature04330. - DOI - PubMed

LinkOut - more resources