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Molecules 2018, 23(2), 340;

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

Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico
Laboratorio de Farmacología, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana Iztapalapa, Ciudad de México 09340, Mexico
Cátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, Yucatán 97310, Mexico
CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, (Z.W.)
Dipartimento di Biologia, Unità di Biochimica, University of Pisa, 56126 Pisa, Italy
Taking in part of the Ph.D. Thesis of Blanca Colín-Lozano.
Author to whom correspondence should be addressed.
Received: 8 January 2018 / Revised: 1 February 2018 / Accepted: 3 February 2018 / Published: 6 February 2018
(This article belongs to the Section Medicinal Chemistry)
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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 (PPARγ) and solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT-4). Compound 1 displayed an EC50 value of 0.075 μM against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7.4 μM. 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 PPARγ, 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 13 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. View Full-Text
Keywords: diabetes; GPR40; AKRB1; PPARγ, GLUT-4 diabetes; GPR40; AKRB1; PPARγ, GLUT-4

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Colín-Lozano, B.; Estrada-Soto, S.; Chávez-Silva, F.; Gutiérrez-Hernández, A.; Cerón-Romero, L.; Giacoman-Martínez, A.; Almanza-Pérez, J.C.; Hernández-Núñez, E.; Wang, Z.; Xie, X.; Cappiello, M.; Balestri, F.; Mura, U.; Navarrete-Vazquez, G. Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids. Molecules 2018, 23, 340.

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