Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids

doi:10.3390/molecules23020340

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	Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids
	Colin-Lozano, Blanca 2; Estrada-Soto, Samuel 2; Chavez-Silva, Fabiola 2; Gutierrez-Hernandez, Abraham 2; Ceron-Romero, Litzia 2; Giacoman-Martinez, Abraham 5; Cesar Almanza-Perez, Julio 5; Hernandez-Nunez, Emanuel 1; Wang, Zhilong 4; Xie, Xin4
刊名	MOLECULES
	2018-02
卷号	23 期号:2
关键词	diabetes GPR40 AKRB1 PPAR gamma GLUT-4
ISSN号	1420-3049
DOI	10.3390/molecules23020340
文献子类	Article
英文摘要	We have synthesized a small series of five 3-[4-arylmethoxy) phenyl] propanoic acids employing an easy and short synthetic pathway. The compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: G protein-coupled receptor 40 (GPR40), aldose reductase (AKR1B1), peroxisome proliferator-activated receptor gama (PPAR gamma) and solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT-4). Compound 1 displayed an EC50 value of 0.075 mu M against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7.4 mu M. Compounds 2 and 3 act as slightly AKR1B1 inhibitors, potent GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPAR gamma, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active molecules on these targets, showing several coincidences with co-crystal ligands. Compounds 1-3 were tested in vivo at an explorative 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non-insulin-dependent diabetes mice model. Compounds 2 and 3 displayed robust in vitro potency and in vivo efficacy, and could be considered as promising multitarget antidiabetic candidates. This is the first report of a single molecule with these four polypharmacological target action.
资助项目	Consejo Nacional de Ciencia y Tecnologia (CONACyT)[253814] ; CONACYT fellowship[378373]
WOS关键词	ALDOSE REDUCTASE-ACTIVITY ; IN-SILICO ; POLYOL PATHWAY ; PPAR-GAMMA ; BETA-CELL ; DISCOVERY ; GPR40 ; AGONISTS ; DRUG ; STREPTOZOTOCIN
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	MDPI
WOS记录号	WOS:000426436300120
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279919]
专题	国家新药筛选中心
通讯作者	Navarrete-Vazquez, Gabriel
作者单位	1.IPN, Ctr Invest & Estudios Avanzados, Dept Recursos Mar, Catedra CONACyT, Merida 97310, Yucatan, Mexico; 2.Univ Autonoma Estado Morelos, Fac Farm, Cuernavaca 62209, Morelos, Mexico; 3.Univ Pisa, Unita Biochim, Dipartimento Biol, I-56126 Pisa, Italy 4.Chinese Acad Sci, CAS Key Lab Receptor Res, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 5.Univ Autonoma Metropolitana Iztapalapa, Dept Ciencias Salud, Lab Farmacol, Mexico City 09340, DF, Mexico;
推荐引用方式 GB/T 7714	Colin-Lozano, Blanca,Estrada-Soto, Samuel,Chavez-Silva, Fabiola,et al. Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids[J]. MOLECULES,2018,23(2).
APA	Colin-Lozano, Blanca.,Estrada-Soto, Samuel.,Chavez-Silva, Fabiola.,Gutierrez-Hernandez, Abraham.,Ceron-Romero, Litzia.,...&Navarrete-Vazquez, Gabriel.(2018).Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids.MOLECULES,23(2).
MLA	Colin-Lozano, Blanca,et al."Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids".MOLECULES 23.2(2018).