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Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide
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    Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide
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    Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2015, 58, 18, 7370–7380
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    https://doi.org/10.1021/acs.jmedchem.5b00726
    Published August 26, 2015
    Copyright © 2015 American Chemical Society

    Abstract

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    Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once weekly GLP-1 analogue by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analogue. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib8, Arg34) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs. Semaglutide is currently in phase 3 clinical testing.

    Copyright © 2015 American Chemical Society

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    • Tables of all peptides with analysis as well as data and refinement statistics for the structure (PDF)

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    Cited By

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    This article is cited by 615 publications.

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    Cite this: J. Med. Chem. 2015, 58, 18, 7370–7380
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    https://doi.org/10.1021/acs.jmedchem.5b00726
    Published August 26, 2015
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