title: Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance.
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.
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Wiśniewski
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Javier
authors.initials: J
authors.lastname: Sueiras-Diaz
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Guangcheng
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Galyean
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Lu
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Dorain
authors.initials: D
authors.lastname: Thompson
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Yung-Chih
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Glenn
authors.initials: G
authors.lastname: Croston
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Posch
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Hargrove
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Halina
authors.initials: H
authors.lastname: Wiśniewska
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Régent
authors.initials: R
authors.lastname: Laporte
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Dwyer
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Qi
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Karthik
authors.initials: K
authors.lastname: Srinivasan
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hartwig
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Nicky
authors.initials: N
authors.lastname: Ferdyan
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Mares
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: John
authors.initials: J
authors.lastname: Kraus
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Sudarkodi
authors.initials: S
authors.lastname: Alagarsamy
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Pierre J M
authors.initials: PJ
authors.lastname: Rivière
authors.affiliation: Ferring Research Institute Inc., 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States.
authors.forename: Claudio D
authors.initials: CD
authors.lastname: Schteingart
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D053767:Glucagon-Like Peptide 2 / Q000819:agonists* / Q000737:chemistry; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D000067758:Glucagon-Like Peptide-2 Receptor / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000254:growth & development; D008297:Male; D008969:Molecular Sequence Data; D009646:Norleucine / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C000593833:GLP1R protein, human; D053767:Glucagon-Like Peptide 2; D000067757:Glucagon-Like Peptide-1 Receptor; D000067758:Glucagon-Like Peptide-2 Receptor; D010455:Peptides; D009646:Norleucine