Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists

Dehmlow, Henrietta; Sánchez, Rubén Alvarez; Bachmann, Stephan; Bissantz, Caterina; Bliss, Fritz; Conde-Knape, Karin; Gräf, Martin; Martin, Rainer E.; Sander, Ulrike Obst; Raab, Susanne; Richter, Hans G.; Sewing, Sabine; Sprecher, Urs; Ullmer, Christoph; Mattei, Patrizio

doi:10.1016/j.bmcl.2013.06.017

Cited by 11 publications

(7 citation statements)

References 30 publications

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“…Oxime 92a was identified in a high throughput screening campaign as a full agonist with EC 50 values of 45 nM and 2.0 μM at recombinant (CHO-expressed) human and mouse TGR5, respectively (Scheme 34). 87 Initial SAR data around 92a revealed that replacing the 4-pyridyl headgroup by 2-or 3pyridyl, phenyl, or 4-fluorophenyl was not tolerated. o-Methylation was also found less favorable.…”

Section: Tgr5 Agonistsmentioning

confidence: 99%

Recent Progress on Bile Acid Receptor Modulators for Treatment of Metabolic Diseases

2016

J. Med. Chem.

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Bile acids are steroid-derived molecules synthesized in the liver, secreted from hepatocytes into the bile canaliculi, and subsequently stored in the gall bladder. During the feeding, bile flows into the duodenum, where it contributes to the solubilization and digestion of lipid-soluble nutrients. After a meal, bile-acid levels increase in the intestine, liver, and also in the systemic circulation. Therefore, serum bile-acid levels serve as an important sensing mechanism for nutrient and energy. Recent studies have described bile acids as versatile signaling molecules endowed with systemic endocrine functions. Bile acids are ligands for G-protein coupled receptors (GPCRs) such as TGR5 (also known as GPBAR1, M-BAR, and BG37) and nuclear hormone receptors including farnesoid X receptor (FXR; also known as NR1H4). Acting through these diverse signaling pathways, bile acids regulate triglyceride, cholesterol, glucose homeostasis, and energy expenditure. These bile-acid-controlled signaling pathways have become the source of promising novel drug targets to treat common metabolic and hepatic diseases.

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Section: Tgr5 Agonistsmentioning

confidence: 99%

Recent Progress on Bile Acid Receptor Modulators for Treatment of Metabolic Diseases

2016

J. Med. Chem.

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“…The residue was purified by preparative HPLC (Waters Sunfire C18 OBD 18 mm × 60 mm, flow 20 mL/min, water + 0.1% TFA and acetonitrile + 0.1% TFA gradient) to give the title compound 13 (76 mg, 0.18 mmol, 60%). 1 N-(3,5-Dichlorophenyl)-N-(2-methoxybenzyl)-3-methylisonicotinamide (14). 1-Chloro-N,N,2-trimethylpropenylamine (320 μL, 2.42 mmol) was added to a solution of 3-methylisonicotinic acid (150 mg, 1.09 mmol) in dry dichloromethane (10 mL), and the resulting mixture was stirred for 45 min at rt.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…GPBAR1 was found to be involved in lipid and glucose metabolism as well as energy expenditure, and in this context, receptor agonists are being pursued by various pharmaceutical companies to offer treatment options for conditions such as obesity, hypercholesterolemia, hypertriglyceridemia, and nonalcoholic steatohepatitis . Most importantly, the finding that GPBAR1 agonism induces the secretion of clinically relevant glucagon-like peptide 1 (GLP-1) raised expectations of an alternative therapeutic mechanism for the treatment of type 2 diabetes mellitus and triggered extensive research efforts. − …”

Section: Introductionmentioning

confidence: 99%

G-Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5) Agonists Reduce the Production of Proinflammatory Cytokines and Stabilize the Alternative Macrophage Phenotype

Högenauer¹,

Arista²,

Schmiedeberg³

et al. 2014

J. Med. Chem.

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GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-α and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-α and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation.

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“…A medical solution to reproducing the gut hormone response observed after bariatric surgery in the portal circulation, opposed to systemically, could be a more progressive approach. For example, orally administered G-protein-coupled bile acid receptor-1 agonists have recently been employed as L-cell activators (30). Understanding the complex interplay between GLP-1 and its counterpart PYY, as well as their hepatoportal dynamics, could also lead to more effective gut hormone-based therapies for T2D and obesity.…”

Section: Discussionmentioning

confidence: 99%

GLP-1: A Mediator of the Beneficial Metabolic Effects of Bariatric Surgery?

2015

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Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists

Cited by 11 publications

References 30 publications

Recent Progress on Bile Acid Receptor Modulators for Treatment of Metabolic Diseases

Recent Progress on Bile Acid Receptor Modulators for Treatment of Metabolic Diseases

G-Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5) Agonists Reduce the Production of Proinflammatory Cytokines and Stabilize the Alternative Macrophage Phenotype

GLP-1: A Mediator of the Beneficial Metabolic Effects of Bariatric Surgery?

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