Yangliang Ye

Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes

Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 Å(2), and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.

Discovery of novel dual functional agent as PPARγ agonist and 11β-HSD1 inhibitor for the treatment of diabetes

PPARgamma and 11beta-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARgamma agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11beta-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of alpha-aryloxy-alpha-methylhydrocinnamic acids as dual functional agents which activate PPARgamma and inhibit 11beta-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARgamma (EC(50)=6.76 microM) and 11beta-HSD1 (IC(50)=0.76 microM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile.

Design, synthesis, and structure-activity relationships of 3,4,5-trisubstituted 4,5-dihydro-1,2,4-oxadiazoles as TGR5 agonists.

Given its role in the mediation of energy and glucose homeostasis, the G‐protein‐coupled bile acid receptor 1 (TGR5) is considered a potential target for the treatment of type 2 diabetes mellitus and other metabolic disorders. By thorough analysis of diverse structures of published TGR5 agonists, a hypothetical ligand‐based pharmacophore model was built, and a new class of potent TGR5 agonists, based on the novel 3,4,5‐trisubstituted 4,5‐dihydro‐1,2,4‐oxadiazole core, was discovered by rational design. Three distinct synthetic methods for constructing 4,5‐dihydro‐1,2,4‐oxadiazoles and extensive structure–activity relationship studies are reported herein. Compound (R)‐54 n, the structure of which was determined by single‐crystal X‐ray diffraction and quantum chemical solid‐state TDDFT‐ECD calculations, showed the best potency, with an EC50 value of 1.4 nM toward hTGR5. Its favorable properties in vitro warrant further investigation.

Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect

TGR5 activation of enteroendocrine cells increases glucagon-like peptide 1 (GLP-1) release, which maintains glycemic homeostasis. However, TGR5 activation in the gallbladder and heart is associated with severe side effects. Therefore, intestinally-targeted TGR5 agonists were suggested as potential hypoglycemic agents with minimal side effects. However, until now no such compounds with robust glucose-lowering effects were reported, especially in diabetic animal models. Herein, we identify a TGR5 agonist, 26a, which was proven to be intestinally-targeted through pharmacokinetic studies. 26a was used as a tool drug to verify the intestinally-targeted strategy. 26a displayed a robust and long-lasting hypoglycemic effect in ob/ob mice (once a day dosing (QD) and 18-day treatment) owing to sustained stimulation of GLP-1 secretion, which suggested that robust hypoglycemic effect could be achieved with activation of TGR5 in intestine alone. However, the gallbladder filling effect of 26a was rather complicated. Although the gallbladder filling effect of 26a was decreased in mice after once a day dosing, this side effect was still not eliminated. To solve the problem above, several research strategies were raised for further optimization.

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

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 μmol/L). OL3 inhibited human and mouse DPP-4 with IC50 values of 18.44 and 69.98 μmol/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.

Linderane suppresses hepatic gluconeogenesis by inhibiting the cAMP/PKA/CREB pathway through indirect activation of PDE 3 via ERK/STAT3

The role of phosphodiesterase 3 (PDE3), a cyclic AMP (cAMP)-degrading enzyme, in modulating gluconeogenesis remains unknown. Here, linderane, a natural compound, was found to inhibit gluconeogenesis by activating hepatic PDE3 in rat primary hepatocytes. The underlying molecular mechanism and its effects on whole-body glucose and lipid metabolism were investigated. The effect of linderane on gluconeogenesis, cAMP content, phosphorylation of cAMP-response element-binding protein (CREB) and PDE activity were examined in cultured primary hepatocytes and C57BL/6J mice. The precise mechanism by which linderane activates PDE3 and inhibits the cAMP pathway was explored using pharmacological inhibitors. The amelioration of metabolic disorders was observed in ob/ob mice. Linderane inhibited gluconeogenesis, reduced phosphoenolpyruvate carboxykinase (Pck1) and glucose-6-phosphatase (G6pc) gene expression, and decreased intracellular cAMP concentration and CREB phosphorylation in rat primary hepatocytes under both basal and forskolin-stimulated conditions. In rat primary hepatocytes, it also increased total PDE and PDE3 activity but not PDE4 activity. The suppressive effect of linderane on the cAMP pathway and gluconeogenesis was abolished by the non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the specific PDE3 inhibitor cilostazol. Linderane indirectly activated PDE3 through extracellular regulated protein kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) activation. Linderane improved glucose and lipid metabolism after chronic oral administration in ob/ob mice. Our findings revealed linderane as an indirect PDE3 activator that suppresses gluconeogenesis through cAMP pathway inhibition and has beneficial effects on metabolic syndromes in ob/ob mice. This investigation highlighted the potential for PDE3 activation in the treatment of type 2 diabetes.

Design, synthesis and structure−activity relationship studies of GPR40 agonists containing amide linker

Free fatty acid receptor 1 (FFAR1/GPR40) attracted significant attention as a potential target for developing novel antidiabetic drugs because of its unique mechanism in glucose homeostasis. Several reports have expressed concerns about central nervous system (CNS) penetration of GPR40 agonists, which is possibly attributed to their high lipophilicity and low total polar surface area. Herein, we report our efforts to improve the physicochemical properties and pharmacokinetic profiles of LY2881835, a GPR40 agonist that had undergone Phase I clinical trial, through a series of structural optimizations. We identified an orally efficacious compound, 15k, which possessed increased plasma exposure, prolonged half-life and reduced CNS exposure and liver to plasma distribution ratio compared with LY2881835. 15k is a potentially valuable lead compound in the development of safe and efficacious GPR40-targeted drugs to treat type 2 diabetes mellitus.

Orally Administrated Small Molecule Drugs with Intestine Targeted Profile: Recent Development and Prospects

BACKGROUND Intestine targeted drugs are orally administered compounds exerting their therapeutic effects locally in the intestinal tract, thus avoiding side effects related to systemic exposure. OBJECTIVE Both academic and pharmaceutical research has, therefore, focused on such agents, but the systematic methodology needed for their design and evaluation has been unclear. Thus, careful summary of this kind of drugs is vital for drug design. METHOD This review summarizes achievements from 2013 to 2016, through literatures, patents and related websites, in developing orally administrated small molecule drugs with intestine targeted profile. RESULTS This review summarized six categories of intestine targeted drugs, based on various design strategies, with careful analysis of recent examples from each category. CONCLUSION Our analysis indicated that the intestine targeted profile could expand the therapeutic window of drugs while retaining their efficacy. Thus, we describe simple approaches suitable for rational design of intestine targeted drugs.

Discovery and Structure–Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists

A novel therapy that stimulates endogenous glucagon-like peptide-1 (GLP-1) secretion by Takeda G-protein-coupled receptor 5 (TGR5) agonists might be a superior alternative for the treatment of type 2 diabetes mellitus. A series of 4-phenoxythiazol-5-carboxamides were developed as highly potent TGR5 agonists using a bioisosteric replacement strategy based on the scaffold of 4-phenoxynicotinamides. The structure-activity relationship on the bottom phenyl ring and the thiazole ring was extensively studied, and the 2-methyl-thiazole derivatives 30c and e displayed the best in vitro potency toward human TGR5, with EC50 values of approximately 1 nM. While endowed with excellent in vitro potency, the 2-methyl-thiazoles were flawed with high microsomal clearance.