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TGR5 plays an important role in many physiological processes. However, the functions of TGR5 in the regulation of the glucose metabolism and insulin sensitivity in the skeletal muscles have not been fully elucidated. We synthesized MN6 as a potent and selective TGR5 agonist. Here, the effect of MN6 on insulin resistance in skeletal muscles was evaluated in diet-induced obese (DIO) mice and C2C12 myotubes, and the underlying mechanisms were explored. The activation of MN6 on human and mouse TGR5 was evaluated by a cAMP assay in HEK293 cell lines stable expressing hTGR5/CRE or mTGR5/CRE cells. GLP-1 secretion was measured in NCI-H716 cells and CD1 mice. The acute and chronic effects of MN6 on regulating metabolic abnormalities were observed in ob/ob and DIO mice. 2-deoxyglucose uptake was examined in isolated skeletal muscles. Akt phosphorylation, glucose uptake and glycogen synthesis were examined to assess the effects of MN6 on palmitate-induced insulin resistance in C2C12 myotubes. MN6 potently activated human and mouse TGR5 with EC 50 values of 15.9 and 17.9 nmol/L, respectively, and stimulated GLP-1 secretion in NCI-H716 cells and CD1 mice. A single oral dose of MN6 significantly decreased the blood glucose levels in ob/ob mice. Treatment with MN6 for 15 days reduced the fasting blood glucose and HbA1c levels in ob/ob mice. MN6 improved glucose and insulin tolerance and enhanced the insulin-stimulated glucose uptake of skeletal muscles in DIO mice. The palmitate-induced impairment of insulin-stimulated Akt phosphorylation, glucose uptake and glycogen synthesis in C2C12 myotubes could be prevented by MN6. The effect of MN6 on palmitate-impaired insulin-stimulated Akt phosphorylation was abolished by siRNA-mediated knockdown of TGR5 or by the inhibition of adenylate cyclase or protein kinase A, suggesting that this effect is dependent on the activation of TGR5 and the cAMP/PKA pathway. Our study identified that a TGR5 agonist could ameliorate insulin resistance by the cAMP/PKA pathway in skeletal muscles; this uncovered a new effect of the TGR5 agonist on regulating the glucose metabolism and insulin sensitivity in skeletal muscles and further strengthened its potential value for the treatment of type 2 diabetes. • MN6 potently activated TGR5 and stimulated GLP-1 secretion. • MN6 improved glucose homeostasis in ob/ob and DIO mice. • MN6 enhanced insulin-stimulated glucose uptake in skeletal muscles of DIO mice. • MN6 prevented palmitate-induced insulin resistance in C2C12 myotubes. • MN6 ameliorated palmitate-induced insulin resistance by TGR5/cAMP/PKA pathway. [ABSTRACT FROM AUTHOR]

Phenotypic screening still plays an important role in discovering new drugs, especially for diseases with complex pathogenesis, such as diabetes. As excessive gluconeogenesis is considered an important factor in the occurrence of hyperglycemia in T2DM, we previously screened our compounds library for active molecules which inhibit gluconeogenesis, resulting in the discovery of SL010110 with a unique mechanism, different from metformin and a thienopyridine derivative (DMT). The SARs study of SL010110 led to the discovery of 10v. Compared with SL010110 , 10v showed improved anti-gluconeogenesis potency and pyruvate tolerance. A further pharmacokinetic study demonstrated that 10v displayed a relatively short half-life, moderate volume of distribution, and moderate to high oral bioavailability. In vivo chronic experiments showed an improved capability of 10v in ameliorating hyperglycemia as the 5 mg/kg 10v treatment greatly reduced non-fasting and fasting blood glucose levels, making it a promising candidate for the treatment of T2DM. The progression from in vitro screening to in vivo testing of the derivatized compounds provided a useful phenotypic screening drug discovery strategy based on the inhibition of gluconeogenesis. [Display omitted] • Systematic SAR investigation of furan-2-carboxylic acid derivatives. • 10v exhibited best anti-gluconeogenesis potency in vitro among all derivatives. • 10v showed superb pyruvate tolerance and oral bioavailability in vivo. • 10v displayed improved effect on ameliorating hyperglycemia in ob/ob mice. • Both pharmacokinetic and pharmacodynamic of 10v supported its further development. [ABSTRACT FROM AUTHOR]

Persistent activation of hepatic gluconeogenesis is a main cause of fasting hyperglycemia in patients with type 2 diabetes (T2D), and the salt-induced kinase 1 (SIK1) acts as a key modulator in regulating hepatic gluconeogenesis. Recently, we first reported phanginin A (PA, 1), a natural cassane diterpenoid isolated from the seeds of Caesalpinia sappan , exhibited potent anti-diabetic effect through activation of SIK1 and increasing PDE4 activity to inhibit hepatic gluconeogenesis pathway by suppressing the cAMP/PKA/CREB pathway in the liver. In present study, we designed and prepared 25 PA derivatives and their structure−activity relationship (SAR) for gluconeogenesis inhibitory activity were established. Among them, compound 7 exhibited remarkable inhibitory activity on hepatic gluconeogenesis by enhancing the SIK1 phosphorylation and ameliorated the hyperglyceamia of type 2 diabetic mice. Our results supported that compound 7 could be served as a potential candidate for the treatment of T2D. [Display omitted] • Twenty-five phanginin A derivatives were designed and synthesized. • SAR for phanginin A analogues on gluconeogenesis inhibitory activity were discussed. • 7 suppressed gluconeogenesis by activating SIK1 to inhibit cAMP/CREB pathway. • 7 be a potential candidate for the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC50 =0.017μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4=1324; DPP-9/DPP-4=1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague–Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent. [Copyright &y& Elsevier]

Abstract: Dual-target-directed agents simultaneously inhibiting glycogen phosphorylase (GP) and activating glucokinase (GK) could decelerate the inflow of glucose from glycogenolysis and accelerate the outflow of glucose in the liver, therefore allow for a better control over hyperglycaemia in a synergetic manner. A series of hybrid compounds were designed by structure-assisted and ligand-based strategies. In vitro bioassays found two novel compounds (1j, 6g) worthy of further optimization on balance of dual action to GP and GK. In addition, for single-target activity, two compounds exhibited more potent GP inhibitory activity and four compounds showed better GK activation than their corresponding references. [Copyright &y& Elsevier]

Abstract: A series of benzamide derivatives which can simultaneously inhibit glycogen phosphorylase (GP) and activate glucokinase (GK) were prepared and evaluated. The structure–activity relationships (SAR) of these compounds were also presented. Among these, compounds 12, 13l, 13q, and 13v showed moderate activities towards both GK and GP. Compound 13h inhibited hLGP with an IC50 of 8.95μM and activated GK with an EC50 of 1.87μM. The possible binding modes of compounds 12, 13l, 13h, and 13q with GP and GK were also explored by molecular docking simulation. [Copyright &y& Elsevier]

Abstract: PPARγ and 11β-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARγ agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11β-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 α-aryloxy-α-methylhydrocinnamic acids as dual functional agents which activate PPARγ and inhibit 11β-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARγ (EC50 =6.76μM) and 11β-HSD1 (IC50 =0.76μM) 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. [Copyright &y& Elsevier]

Abstract: Selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential as treatments for type 2 diabetes. Presented herein are the syntheses, structure–activity relationships, and efficacy evaluation of 4-(phenylsulfonamidomethyl)benzamides as 11β-HSD1 inhibitors. Through modification of our initial lead 5, we have identified potent and selective 11β-HSD1 inhibitors, such as 11n, which demonstrated improved glycemic control, decreased serum lipids, and enhanced insulin sensitivity when dosed ip in diabetic ob/ob mice. [Copyright &y& Elsevier]

The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 agonists with soft-drug designation had been designed and synthesized with the properties of rapid metabolized after drug effect. Among them, compound 19 showed negligible systemic exposure and favorable gallbladder safety on a 3-day continuous administration, providing a novel strategy for developing TGR5 agonists. Image 1 • Soft-drug TGR5 agonists were first designed, synthesized and evaluated. • 19 could be rapidly metabolized into inactive metabolite after exerting efficacy. • 19 showed negligible systemic exposure and favorable gallbladder safety. • Soft drug strategy is a novel strategy for the development of TGR5 agonists. [ABSTRACT FROM AUTHOR]