Identification of novel orally available small molecule insulin mimetics.
Oral hypoglycemic agents have great potential for the treatment of both type 1 and type 2 diabetes. Here we report the identification of novel, small-molecule, insulin mimetics that activate the insulin receptor (IR) in vivo and in vitro, stimulate the Akt and extracellular signal-regulated kinase pathways downstream of the IR, and mimic the ability of insulin to stimulate glucose uptake, glycogen synthesis, and lipid synthesis in 3T3-L1 adipocytes. However, the compounds do not mimic the mitogenic effect of insulin. In animals, these compounds have oral hypoglycemic effects in both normal C57BL6 mice and diabetic db/db mice. Quantitative structure activity relationship modeling on data from a library of 60 compounds has highlighted structural features that are important for IR agonist activity that can be used to guide design of second and third generation compounds with greater potency and specificity.
Veterans Affairs San Diego Healthcare System and Veterans Medical Research Foundation, San Diego, California, USA.
Bo
B
Lin
Zhitao
Z
Li
Kaapjoo
K
Park
Liu
L
Deng
Ashok
A
Pai
Ling
L
Zhong
Michael C
MC
Pirrung
Nicholas J G
NJ
Webster
D041721:3T3-L1 Cells; D000284:Administration, Oral; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D021281:Quantitative Structure-Activity Relationship; D011972:Receptor, Insulin / Q000187:drug effects*
D016227:Benzoquinones; D007004:Hypoglycemic Agents; D007328:Insulin; D011972:Receptor, Insulin