[2-Sulfo-9-fluorenylmethoxycarbonyl]3-exendin-4-a long-acting glucose-lowering prodrug.
Exendin-4, a glucagon-like peptide-1 agonist, is a relatively short-lived species in the circulatory system in vivo. We have linked three moieties of 2-sulfo-9-fluorenylmethoxycarbonyl (FMS) to the three amino functions of exendin-4. FMS(3)-exendin-4 thus obtained has about 0.1% the glucose-lowering potency of the native peptide. Upon in vitro incubation at physiological conditions, the FMS moieties undergo hydrolysis generating the parent fully active, exendin-4. A single subcutaneous administration of FMS(3)-exendin-4 to healthy and type II diabetic mice has induced a glucose-lowering profile that exceeds in length several times that obtained by the native peptide. The reduction of blood glucose level began 1h after administration and was maximal 3-4h later. The blood glucose level returned to pre-administered values with t(1/2) of 12+/-0.7, 26+/-2, and 44+/-3h with doses of 1, 10, and 100 micro g/mouse, respectively. In sum, we have synthesized and characterized FMS(3)-exendin-4, a prodrug derivative of the native insulinotropic peptide, and found it to facilitate a prolonged and stable, glucose-lowering action in healthy and diabetic mice.
Shechter
Yoram
Y
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100, Israel. y.schechter@wiezmann.ac.il
Tsubery
Haim
H
Fridkin
Mati
M
D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003692:Delayed-Action Preparations; D000077270:Exenatide; D005449:Fluorenes / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D014688:Venoms
C475567:(2-sulfo-9-fluorenylmethoxycarbonyl)3-exendin-4; D001786:Blood Glucose; D003692:Delayed-Action Preparations; D005449:Fluorenes; D007004:Hypoglycemic Agents; D010455:Peptides; D011355:Prodrugs; D014688:Venoms; D000077270:Exenatide