The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus

Guzmán-Pérez, Angel; Pfefferkorn, Jeffrey A.; Lee, Esther C.Y.; Stevens, Benjamin D.; Aspnes, Gary E.; Bian, Jianwei; Didiuk, Mary T.; Filipski, Kevin J.; Moore, Dianna E.; Perreault, Christian; Sammons, M. F.; Tu, Meihua; Brown, Janice A.; Atkinson, Karen; Litchfield, John; Tan, Beijing; Samas, Brian; Zavadoski, William J.; Salatto, Christopher T.; Treadway, Judith L.

doi:10.1016/j.bmcl.2013.03.014

Cited by 37 publications

(13 citation statements)

References 23 publications

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“…Thus, the carbon atoms 3 and 5 exchange their numbering on going from tautomer a to b. There is ample information in the literature that a trifluoromethyl group is an interesting pharmacophore [26,27,28] even in pyrazole derivatives [29,30,31] including the well-known anti-inflammatory Celecoxib [32]. 19 F, nitromethane and CFCl 3 respectively.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1H-pyrazoles derived from hemicurcuminoids

Nieto

Cabildo

Cornago

et al. 2015

Journal of Molecular Structure

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Section: Introductionmentioning

confidence: 99%

Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1H-pyrazoles derived from hemicurcuminoids

Nieto

Cabildo

Cornago

et al. 2015

Journal of Molecular Structure

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“…As a continuation, Lee et al incorporated a cyclic core (pyrrolidine or cyclopentane) to restrain the conformation and developed compound 15 67 , which was disclosed as a novel GCGR antagonist. They replaced the central phenyl ring with a pyrimidine to obtain two enantiomers, (+) 16 and (−) 16 .…”

Section: Small Molecule Gcgr Modulatorsmentioning

confidence: 99%

Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure

et al. 2015

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The glucagon subfamily of class B G protein-coupled receptors (GPCRs) has been proposed to be a crucial drug target for the tretmaent of type 2 diabetes. The challenges associated with determining the crystal structures of class B GPCRs relate to their large amino termini and the lack of available small molecule ligands to stabilize the receptor proteins. Following our discovery of non-peptidic agonists for glucagon-like peptide-1 receptor (GLP-1R) that have therapeutic effects, we initiated collaborative efforts in structural biology and recently solved the three-dimensional (3D) structure of the human glucagon receptor (GCGR) 7-transmembrane domain, providing in-depth information about the underlying signaling mechanisms. In this review, some key milestones in this endeavor are highlighted, including discoveries of small molecule ligands, their roles in receptor crystallization, conformational changes in transmembrane domains (TMDs) upon activation and structure-activity relationship analyses.

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“…The utility of 2H-indazoles as pharmacophore in drug discovery has been exemplified in several recent publications [3][4][5][6] , a substantial research work around the globe enabling the synthesis of such motifs [7][8][9][10] . The planar indazole containing two nitrogen atoms in ring can be functionalized with high selectivity by varying length of side chain and functionalizing at different positions will yield enormous number of indazole derivatives, providing new spectrum of molecules having with therapeutic properties.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Study of 3-Methyl-N-[Arylylmethylene]-1h-Indazol-5-Amines From 2-Hydroxy-4-Amino Acetophenone and Their Anti-Microbial Activity

Sujatha¹,

Rao²,

Khader³

et al. 2020

Int. Res. J. Pharm.

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Indazole is one of the most important scaffolds in heterocyclic chemistry and drug design and discovery. It is rarely found in nature but widely found in diverse pharmacologically active substances. Indazoles are versatile building-block for lead generation, the indazole core is an active pharmacophore and used in medicinal chemistry and drug discovery research. A number of drugs with indazole core are in the market, In the recent years, many indazole derivatives have been synthesized and subjected to varied biological activities. Here indazoles are prepared from 2-hydroxy-4-amino acetophenone, the free amino group is preprotected and reacted with hydrazine hydrate at elevated temperature thus obtained indazoles are deprotected and hydrazone derivatives were prepared, the newly synthesized indazole derivatives were screened for antibacterial and antifungal activity.

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The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus

Cited by 37 publications

References 23 publications

Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1H-pyrazoles derived from hemicurcuminoids

Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1H-pyrazoles derived from hemicurcuminoids

Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure

Synthesis and Study of 3-Methyl-N-[Arylylmethylene]-1h-Indazol-5-Amines From 2-Hydroxy-4-Amino Acetophenone and Their Anti-Microbial Activity

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