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- W2297989013 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 ([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-Phe11,Leu16]hGLP-2-(1−33)-NHEt), and 85 ([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 73 (FE 203799) was selected as a candidate for clinical development." @default.
- W2297989013 created "2016-06-24" @default.
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- W2297989013 date "2016-03-25" @default.
- W2297989013 modified "2023-09-30" @default.
- W2297989013 title "Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance" @default.
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- W2297989013 doi "https://doi.org/10.1021/acs.jmedchem.5b01909" @default.
- W2297989013 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26986178" @default.
- W2297989013 hasPublicationYear "2016" @default.
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