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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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Structures of synthesized compounds. a Synthesized imidazo[1,2-a]pyridine-based molecules. b Other synthesized heterocycle-series compounds
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Fig2: Structures of synthesized compounds. a Synthesized imidazo[1,2-a]pyridine-based molecules. b Other synthesized heterocycle-series compounds

Mentions: Figure 1 shows synthetic small molecule agonists reported by several groups (Teng et al. 2000; Wang et al. 2009; Teng et al. 2007; Kopin 2004; Gong et al. 2010). Compound 6b, characterized by a novel imidazopyridine hit core, was identified from a library of 10,000 heterocyclic small molecules (Gong et al. 2010). As a small and drug-like active molecule, it represents an interesting starting point for the development of novel drugs. Therefore, we selected this compound as a model. In an effort to move away from the labile ester group of the phenol, we planned a synthetic pathway of new derivatives of imidazo[1,2-α]pyridine-based molecules (Fig. 2). To evaluate the structure–activity relationship, we designed and synthesized a series of heterocyclic derivatives containing a ring-junction nitrogen using a three-dimensional (3D) pharmacophore model reported previously (Gong et al. 2010) (Fig. 2). For the first stage, only combinations of five- and six-membered rings are considered, including imidazo[1,5-α]pyridine, imidazo[1,2-α]pyrimidine and imidazo[1,2-α]pyrazine. 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, structurally complex, small molecules.Fig. 1


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)

Structures of synthesized compounds. a Synthesized imidazo[1,2-a]pyridine-based molecules. b Other synthesized heterocycle-series compounds
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4016675&req=5

Fig2: Structures of synthesized compounds. a Synthesized imidazo[1,2-a]pyridine-based molecules. b Other synthesized heterocycle-series compounds
Mentions: Figure 1 shows synthetic small molecule agonists reported by several groups (Teng et al. 2000; Wang et al. 2009; Teng et al. 2007; Kopin 2004; Gong et al. 2010). Compound 6b, characterized by a novel imidazopyridine hit core, was identified from a library of 10,000 heterocyclic small molecules (Gong et al. 2010). As a small and drug-like active molecule, it represents an interesting starting point for the development of novel drugs. Therefore, we selected this compound as a model. In an effort to move away from the labile ester group of the phenol, we planned a synthetic pathway of new derivatives of imidazo[1,2-α]pyridine-based molecules (Fig. 2). To evaluate the structure–activity relationship, we designed and synthesized a series of heterocyclic derivatives containing a ring-junction nitrogen using a three-dimensional (3D) pharmacophore model reported previously (Gong et al. 2010) (Fig. 2). For the first stage, only combinations of five- and six-membered rings are considered, including imidazo[1,5-α]pyridine, imidazo[1,2-α]pyrimidine and imidazo[1,2-α]pyrazine. 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, structurally complex, small molecules.Fig. 1

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