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Synthesis and biological evaluation of glucagon-like peptide-1 receptor agonists.

Zhang YJ, Shen LL, Cheon HG, Xu YN, Jeong JH - Arch. Pharm. Res. (2013)

Bottom Line: We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules.Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application.These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.

ABSTRACT
In this study, a series of fused-heterocyclic derivatives were systematically designed and synthesized using an efficient route, and evaluated in terms of GLP-1R agonist activity. We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules. Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.

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Related in: MedlinePlus

Reagents and conditions: (a) NBS, CH3CN, reflux; (b) dioxane, reflux or NaHCO3, dioxane, reflux; (c) EtOH, reflux
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Sch5: Reagents and conditions: (a) NBS, CH3CN, reflux; (b) dioxane, reflux or NaHCO3, dioxane, reflux; (c) EtOH, reflux

Mentions: The syntheses of compounds 37a–37e are detailed in Scheme 5. The preparation of intermediate 35 was achieved by bromination of 2-aminopyrimidine 34 with NBS in refluxing acetonitrile. The subsequent cyclization of 35, 2-anmonoprimidine 34, and 2-aminopyrazine 36 with intermediate 3 yielded the target derivatives 37a–37c, respectively. The cyclization of 2-anmonoprimidine 34 and 2-aminopyrazine 36 with intermediate 29 yielded the target derivatives 37d–37e, respectively.Scheme 5


Synthesis and biological evaluation of glucagon-like peptide-1 receptor agonists.

Zhang YJ, Shen LL, Cheon HG, Xu YN, Jeong JH - Arch. Pharm. Res. (2013)

Reagents and conditions: (a) NBS, CH3CN, reflux; (b) dioxane, reflux or NaHCO3, dioxane, reflux; (c) EtOH, reflux
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4016675&req=5

Sch5: Reagents and conditions: (a) NBS, CH3CN, reflux; (b) dioxane, reflux or NaHCO3, dioxane, reflux; (c) EtOH, reflux
Mentions: The syntheses of compounds 37a–37e are detailed in Scheme 5. The preparation of intermediate 35 was achieved by bromination of 2-aminopyrimidine 34 with NBS in refluxing acetonitrile. The subsequent cyclization of 35, 2-anmonoprimidine 34, and 2-aminopyrazine 36 with intermediate 3 yielded the target derivatives 37a–37c, respectively. The cyclization of 2-anmonoprimidine 34 and 2-aminopyrazine 36 with intermediate 29 yielded the target derivatives 37d–37e, respectively.Scheme 5

Bottom Line: We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules.Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application.These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.

ABSTRACT
In this study, a series of fused-heterocyclic derivatives were systematically designed and synthesized using an efficient route, and evaluated in terms of GLP-1R agonist activity. We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules. Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.

Show MeSH
Related in: MedlinePlus