Synthesis and biological investigations of nitric oxide releasing nateglinide and meglitinide type II antidiabetic prodrugs: in-vivo antihyperglycemic activities and blood pressure lowering studies.
A new group of hybrid nitric oxide-releasing type II antidiabetic drugs possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (13 and 18), 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (14 and 19), or nitrooxyethyl (15 and 20) moiety attached to the carboxylic acid group of the type II antidiabetic drugs nateglinide and meglitinide were synthesized. These prodrugs, based on the beneficial properties of nitric oxide (NO), were designed to reduce the risk of adverse cardiovascular events in diabetic patients. Ester prodrugs (13-15 and 18-20) exhibited appreciable oral antihyperglycemic activity comparable to the parent drugs in nonfasted diabetic rats. Systolic and diastolic blood pressure profiles validated the beneficial hypotensive properties of these prodrugs. These prodrugs released NO (1.3-72.2% range) upon incubation with either phosphate buffer solution at pH 7.4 or in the presence of serum. This new type of hybrid NO donor prodrug represents an attractive approach for the rational design of type II antidiabetic drugs with a reduced risk of contraindicated cardiovascular events.
University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
Jatinder
J
Kaur
Atul
A
Bhardwaj
Zhangjian
Z
Huang
Deepak
D
Narang
Ting-Yueh
TY
Chen
Frances
F
Plane
Edward E
EE
Knaus
D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D003510:Cyclohexanes / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009682:Magnetic Resonance Spectroscopy; D000077715:Nateglinide; D009569:Nitric Oxide / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011355:Prodrugs / Q000627:therapeutic use*; D021241:Spectrometry, Mass, Electrospray Ionization
D001549:Benzamides; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D011355:Prodrugs; D009569:Nitric Oxide; D000077715:Nateglinide; D010649:Phenylalanine; C030516:meglitinide