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. <i>In vitro</i> 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 <b>69</b> ([Gly²,Nle¹⁰,d-Thi¹¹,Phe¹⁶]­hGLP-2-(1−30)-NH₂), <b>72</b> ([Gly²,Nle¹⁰,d-Phe¹¹,Leu¹⁶]­hGLP-2-(1−33)-OH), <b>73</b> ([Gly²,Nle¹⁰,d-Phe¹¹,Leu¹⁶]­hGLP-2-(1−33)-NH₂), <b>81</b> ([Gly²,Nle¹⁰,d-Phe¹¹,Leu¹⁶]­hGLP-2-(1−33)-NHEt), and <b>85</b> ([Gly²,Nle¹⁰,d-Phe¹¹,Leu¹⁶]­hGLP-2-(1−33)-NH-((CH₂)₂O)₄-(CH₂)₂-CONH₂) displayed the desired profiles (EC₅₀ (hGLP-2R) < 100 pM, CL in rat <0.3 mL/min/kg, selective vs hGLP-1R and hGCGR). Compound <b>73</b> (FE 203799) was selected as a candidate for clinical development