Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance

Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized. In vitro receptor potency at the human GLP-2, selectivity vs the human GLP-1 and GCG receptors, and PK profile in rats were determined for the new analogues. A number of compounds more potent at the hGLP-2R than the native hormone, showing excellent receptor selectivity and very low systemic clearance (CL) were discovered. Analogues 69 ([Gly2,Nle10,d-Thi11,Phe16]hGLP-2-(1−30)-NH2), 72 ([Gly2,Nle10,d-Phe11,Leu16]hGLP-2-(1−33)-OH), 73 ([Gly2,Nle10,d-Phe11,Leu16]hGLP-2-(1−33)-NH2), 81 ([Gly2,Nle10,d...