关注GLP-1，改善2型糖尿病的治疗.ppt

* Liraglutide (NN2211) is a long-acting GLP-1 analogue In creating liraglutide, two modifications to the amino acid sequence of GLP-1 are made: a fatty acid is acylated to lysine at position 26 and the lysine at position 34 is replaced with arginine. These modifications result in increased self-association (which slows absorption from the subcutaneous depot), albumin binding and reduced susceptibility to DPP-IV, which combine to prolong its plasma half-life, protracting its action. Thus, the problem of the short half-life, which is the major clinical drawback of native GLP-1, is overcome. For comparison, the plasma half-life of exenatide is 4 to 6 hours (reviewed in Nauck and Drucker, 2006) References Knudsen et al, J Med Chem 2000;43:1664–1669 *include in notes comparison to other natural hormones that are given in pharmaceutical doses and result in therapeutic benefits Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. A series of very potent derivatives of the 30-amino acid peptide hormone glucagon-like peptide-1 (GLP-1) is described. The compounds were all derivatized with fatty acids in order to protract their action by facilitating binding to serum albumin. GLP-1 had a potency (EC(50)) of 55 pM for the cloned human GLP-1 receptor. Many of the compounds had similar or even higher potencies, despite quite large substituents. All compounds derivatized with fatty acids equal to or longer than 12 carbon atoms were very protracted compared to GLP-1 and thus seem suitable for once daily administration to type 2 diabetic patients. A structure-activity relationship was obtained. GLP-1 could be derivatized with linear fatty acids up to the length of 16 carbon atoms, sometimes longer, almost anywhere in the C-terminal part without considerable loss of potency. Derivatization with two fatty acid substituents led to a considerable loss of potency. A structure-activity relationship on derivatization