title: Novel, non-peptidic somatostatin receptor subtype 5 antagonists improve glucose tolerance in rodents.
abstract: BACKGROUND
  Somatostatin regulates numerous endocrine processes, including glucose homeostasis. The contribution and effects of the 5 somatostatin receptors are still unclear, in part due to the lack of suitable subtype specific receptor antagonists. We explored the effects of two novel, non-peptidic, orally bioavailable somatostatin receptor subtype 5 antagonists named Compound A and Compound B on glycemia in animal models of type 2 diabetes after an initial in vitro characterization.
  
  
  RESULTS
  Compound A led to a dose-dependent decrease in glucose and insulin excursions during an OGTT in Zucker (fa/fa) rats after single treatment by up to 17% and 49%, respectively. Diet-induced obese mice showed after three weeks treatment with compounds A and B a dose-dependent decrease of the glucose excursion of up to 45% and 37%, respectively. In contrast to the acute effect observed in Zucker rats, Compound A showed a dose-dependent insulin increase by up to 72%, whereas body weight, liver triglycerides, ALT and AST were dose-dependently decreased.
  
  
  CONCLUSIONS
  SSTR5 antagonists have the potential for short- and long-term improvements of the glucose homeostasis in rodent models of type 2 diabetes. Further work on the mechanism and the relevance for human disease is warranted.
authors.affiliation: Discovery Research, Chemistry and Non-Clinical Safety, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Sprecher
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
authors.forename: Rainer E
authors.initials: RE
authors.lastname: Martin
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Maerki
authors.forename: Rubén Alvarez
authors.initials: RA
authors.lastname: Sanchez
authors.forename: Alfred
authors.initials: A
authors.lastname: Binggeli
authors.forename: Basil
authors.initials: B
authors.lastname: Künnecke
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Christ
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D011924:Rats, Zucker; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D017481:Receptors, Somatostatin; D014280:Triglycerides; C094573:somatostatin receptor 5