Discovery Of Somatostatin Receptor 5 Antagonists

Gastrointestinal hormones play an important role in a variety of key tissues involved in the regulation of systemic metabolism,such as the gastrointestinal tract,pancreas,liver,adipose tissue,and central nervous system.Drug development for chronic metabolic diseases based on glucagon-like peptide 1(GLP-1)has been proven to be an effective strategy.The synergetic effect of multiple gastrointestinal hormones is expected to further improve drug efficacy.Somatostatin receptor 5(SSTR5)is an inhibitory G-protein(Gi)coupled receptor that is mainly expressed in the gastrointestinal tract,pancreatic islets and pituitary.Activation of SSTR5 in the gastrointestinal tract inhibits the secretion of hormones,such as GLP-1,GIP,PYY and CCK.Activation of SSTR5 in pancreatic islets mainly inhibits the secretion of insulin.Antagonizing SSTR5 can promote the release of gastrointestinal hormones and insulin,and then participate in the regulation of energy metabolism and gallbladder emptying.Therefore,SSTR5 antagonists are expected to become new treatments for chronic metabolic diseases such as type 2 diabetes and gallbladder disease.In this paper,we first explored a variety of SSTR5 antagonist skeleton based on4-aminomethylpiperidine lead structures.A new 4-fluoro-4-hydroxymethylpiperidine skeletons were obtained with high antagonistic effect,among which compound F5 and F6 have nanomolar activities in vitro.Subsequent studies on the tail fragment of SSTR5 antagonists with these skeletons identified a monoaryl tail fragment,kept the balance of activity and metabolic stability.Further structural optimization based on conformational restriction strategy,we obtained a highly active spiro scaffolds,in which compound H3 antagonized human SSTR5(h SSTR5,IC50: 0.84 n M)and murine SSTR5(m SSTR5,IC50: 0.13 n M)with subnanomolar activity.Compound I2 was obtained through the attempts to optimize the drug likeness of compound H3.Compound I2 had an antagonistic IC50 of 12 n M and 9.2 n M for h SSTR5 and m SSTR5 respectively,and had no inhibitory effect on h ERG potassium channel(IC50 >40 μM),metabolically stable in-vitro/in-vivo as well.In normal C57BL/6J mice,30mg/kg of compound I2 has a significant hypoglycemic effect in the OGTT experiment,which can reduce the blood glucose ΔAUC by about 45%.In the gallbladder emptying experiment of C57BL/6J mice at 30 mg/kg,the gallbladder weight can be reduced by about 60% after administration of compound I2 compared with the vehicle group.Compound I2 has performed well in the current in vitro and in vivo pharmacokinetics,efficacy and safety evaluations,and can be used as a candidate compound for further research.Attempts in this paper lays the foundation for the development of SSTR5 antagonists,as well as the research and application of SSTR5 antagonists in related diseases.