Metabolism-based approaches for autosomal dominant polycystic kidney disease.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) leads to end stage kidney disease (ESKD) through the development and expansion of multiple cysts throughout the kidney parenchyma. An increase in cyclic adenosine monophosphate (cAMP) plays an important role in generating and maintaining fluid-filled cysts because cAMP activates protein kinase A (PKA) and stimulates epithelial chloride secretion through the cystic fibrosis transmembrane conductance regulator (CFTR). A vasopressin V2 receptor antagonist, Tolvaptan, was recently approved for the treatment of ADPKD patients at high risk of progression.

A FFAR1 full agonist restores islet function in models of impaired glucose-stimulated insulin secretion and diabetic non-human primates.

The free fatty acid receptor 1 (FFAR1/GPR40) mediates fatty acid-induced insulin secretion from pancreatic β-cells. At least 3 distinct binding sites exist on the FFAR1 receptor and numerous synthetic ligands have been investigated for their anti-diabetic actions. Fasiglifam, binds to site-1 and stimulates intra-cellular calcium release and improves glycemic control in diabetic patients.

Discovery and Optimization of 7-Alkylidenyltetrahydroindazole-Based Acylsulfonamide EP3 Antagonists.

A novel series of 7-alkylidenyltetrahydroindazole-based acylsulfonamides were discovered as potent EP3 antagonists. The initial lead compound exhibited potent in vitro EP3 inhibitory activity and good selectivity against other EP receptors. In addition, compound demonstrated in vivo activity in a rat ivGTT model, reversing the suppressive effect of the EP3-specific agonist sulprostone on glucose-stimulated insulin secretion.

GRK Inhibition Potentiates Glucagon-Like Peptide-1 Action.

The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3.

Discovery of a Novel Series of Pyridone-Based EP3 Antagonists for the Treatment of Type 2 Diabetes.

A novel series of pyridones were discovered as potent EP3 antagonists. Optimization guided by EP3 binding and functional assays as well as by eADME and PK profiling led to multiple compounds with good physical properties, excellent oral bioavailability, and a clean in vitro safety profile. Compound was identified as a lead compound as evidenced by the reversal of sulprostone-induced suppression of glucose-stimulated insulin secretion in INS 1E β-cells in vitro and in a rat ivGTT model in vivo.

Persistent or Transient Human β Cell Dysfunction Induced by Metabolic Stress: Specific Signatures and Shared Gene Expression with Type 2 Diabetes.

Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination.

GPR40-Mediated G12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets.

GPR40 is a clinically validated molecular target for the treatment of diabetes. Many GPR40 agonists have been identified to date, with the partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due to off-target liver toxicity. Since then, attention has shifted toward the development of full agonists that exhibit superior efficacy in preclinical models.

Triphenylphosphine oxide is a potent and selective inhibitor of the transient receptor potential melastatin-5 ion channel.

Transient receptor potential melastatin-5 (TRPM5) is a calcium-gated monovalent cation channel expressed in highly specialized cells of the taste bud and gastrointestinal tract, as well as in pancreatic β-cells. Well established as a critical signaling protein for G protein-coupled receptor-mediated taste pathways, TRPM5 also has recently been implicated as a regulator of incretin and insulin secretion. To date, no inhibitors of practical use have been described that could facilitate investigation of TRPM5 functions in taste or secretion of metabolic hormones.

Evaluation of different alpha-Galactosyl glycoconjugates for use in xenotransplantation.

Porcine organs are rapidly rejected after transplantation into primate recipients due to the presence of preexisting immunoglobulins that bind to terminal galactose alpha1,3 galactose residues (alpha-galactosyl) present on porcine glycoproteins and glycolipids. Currently available immunosuppressive reagents have been largely ineffective at controlling the synthesis of these anti-Gal antibodies. Nonantigenic hapten polymers have been shown to be effective materials for blocking humoral immune responses in various model systems.