title: S 50131 and S 51434, two novel small molecule glucokinase activators, lack chronic efficacy despite potent acute antihyperglycaemic activity in diabetic mice.
abstract: OBJECTIVE
  Small molecule glucokinase activators (GKAs) have been associated with potent antidiabetic efficacy and hepatic steatosis in rodents. This study reports the discovery of S 50131 and S 51434, two novel GKAs with an original scaffold and an atypical pharmacological profile.
  
  
  METHODS
  Activity of the compounds was assessed in vitro by measuring activation of recombinant glucokinase, stimulation of glycogen synthesis in rat hepatocytes and increased insulin secretion from rat pancreatic islets of Langerhans. Efficacy and safety in vivo were evaluated after oral administration in db/db mice by measuring glycaemia, HbA1c and dyslipidaemia-associated events.
  
  
  RESULTS
  S 50131 and S 51434 activated GK and stimulated glycogen synthesis in hepatocytes and insulin secretion from pancreatic islets. Unexpectedly, while both compounds effectively lowered glycaemia after acute oral administration, they did not decrease HbA1c after a 4-week treatment in db/db mice. This lack of antidiabetic efficacy was associated with increased plasma free fatty acids (FFAs), contrasting with the effect of GKA50 and N00236460, two GKAs with sustained HbA1c lowering activity but neutral regarding plasma FFAs. S 50131, but not S 51434, also induced hepatic steatosis, as did GKA50 and N00236460. However, a shorter, 4-day treatment resulted in increased hepatic triglycerides without changing the plasma FFA levels, demonstrating dynamic alterations in the lipid profile over time.
  
  
  CONCLUSIONS
  In addition to confirming the occurrence of dyslipidaemia with GKAs, these findings provide new insights into understanding how such compounds may sustain or lose efficacy over time.
authors.affiliation: Department of Metabolic Diseases, Institut de Recherches Servier, Suresnes, France. frederic.deceuninck@fr.netgrs.com
authors.forename: Frédéric
authors.initials: F
authors.lastname: De Ceuninck
authors.forename: Catherine
authors.initials: C
authors.lastname: Kargar
authors.forename: Yves
authors.initials: Y
authors.lastname: Charton
authors.forename: Solo
authors.initials: S
authors.lastname: Goldstein
authors.forename: Françoise
authors.initials: F
authors.lastname: Perron-Sierra
authors.forename: Catherine
authors.initials: C
authors.lastname: Ilic
authors.forename: Audrey
authors.initials: A
authors.lastname: Caliez
authors.forename: Jean-Olivier
authors.initials: JO
authors.lastname: Rolin
authors.forename: Marjorie
authors.initials: M
authors.lastname: Sadlo
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Harley
authors.forename: Cédric
authors.initials: C
authors.lastname: Vinson
authors.forename: Alain
authors.initials: A
authors.lastname: Ktorza
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D018938:Caco-2 Cells; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005941:Glucokinase / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D007408:Intestinal Absorption; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009539:Nicotinic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D011083:Polycyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016896:Treatment Outcome; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002784:Cholesterol; D020536:Enzyme Activators; D005230:Fatty Acids, Nonesterified; D005941:Glucokinase; D006442:Glycated Hemoglobin; D006003:Glycogen; D007004:Hypoglycemic Agents; D007328:Insulin; D009539:Nicotinic Acids; D011083:Polycyclic Compounds; D014280:Triglycerides; C000596272:S 50131; C000596273:S 51434