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

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• 作者：Kazimierz Wiśniewski ; Javier Sueiras-Diaz ; Guangcheng Jiang ; Robert Galyean ; Mark Lu ; Dorain Thompson ; Yung-Chih Wang ; Glenn Croston ; Alexander Posch ; Diane M. Hargrove ; Halina Wiśniewska ; Régent Laporte ; John J. Dwyer ; Steve Qi ; Karthik Srinivasan ; Jennifer Hartwig ; Nicky Ferdyan ; Monica Mares ; John Kraus ; Sudarkodi Alagarsamy ; Pierre J. M. Rivière ; Claudio D. Schteingart
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3129-3139
• 全文大小：410K
• 年卷期：0
• ISSN：1520-4804

文摘

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<sup>2sup>,Nle<sup>10sup>,<span class="smallcaps">dspan>-Thi<sup>11sup>,Phe<sup>16sup>]hGLP-2-(1−30)-NH<sub>2sub>), 72 ([Gly<sup>2sup>,Nle<sup>10sup>,<span class="smallcaps">dspan>-Phe<sup>11sup>,Leu<sup>16sup>]hGLP-2-(1−33)-OH), 73 ([Gly<sup>2sup>,Nle<sup>10sup>,<span class="smallcaps">dspan>-Phe<sup>11sup>,Leu<sup>16sup>]hGLP-2-(1−33)-NH<sub>2sub>), 81 ([Gly<sup>2sup>,Nle<sup>10sup>,<span class="smallcaps">dspan>-Phe<sup>11sup>,Leu<sup>16sup>]hGLP-2-(1−33)-NHEt), and 85 ([Gly<sup>2sup>,Nle<sup>10sup>,<span class="smallcaps">dspan>-Phe<sup>11sup>,Leu<sup>16sup>]hGLP-2-(1−33)-NH-((CH<sub>2sub>)<sub>2sub>O)<sub>4sub>-(CH<sub>2sub>)<sub>2sub>-CONH<sub>2sub>) displayed the desired profiles (EC<sub>50sub> (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.