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

  • J Med Chem. 2016 Apr 14;59(7):3129-39. doi: 10.1021/acs.jmedchem.5b01909.
Kazimierz Wiśniewski  1 ,  Javier Sueiras-Diaz  1 ,  Guangcheng Jiang  1 ,  Robert Galyean  1 ,  Mark Lu  1 ,  Dorain Thompson  1 ,  Yung-Chih Wang  1 ,  Glenn Croston  1 ,  Alexander Posch  1 ,  Diane M Hargrove  1 ,  Halina Wiśniewska  1 ,  Régent Laporte  1 ,  John J Dwyer  1 ,  Steve Qi  1 ,  Karthik Srinivasan  1 ,  Jennifer Hartwig  1 ,  Nicky Ferdyan  1 ,  Monica Mares  1 ,  John Kraus  1 ,  Sudarkodi Alagarsamy  1 ,  Pierre J M Rivière  1 ,  Claudio D Schteingart  1
Affiliations
  • 1. Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
PMID: 26986178 DOI: 10.1021/acs.jmedchem.5b01909
Abstract

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 ([Gly(2),Nle(10),D-Thi(11),Phe(16)]hGLP-2-(1-30)-NH2), 72 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-OH), 73 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH2), 81 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NHEt), and 85 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]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 73 (FE 203799) was selected as a candidate for clinical development.