Preprint Article Version 1 This version not peer reviewed

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

Version 1 : Received: 8 January 2018 / Approved: 9 January 2018 / Online: 9 January 2018 (08:54:18 CET)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Molecules 2018, 23, 340
DOI: 10.3390/molecules23020340

Abstract

We synthesized a small series of five 3-[4-arylmethoxy)phenyl]propanoic acids using an easy and short step synthetic route. All compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: GPR40, aldose reductase (AKR1B1), PPARγ and 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 behave as AKR1B1 inhibitors, 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 compounds on these targets. Compounds 1-3 were tested in vivo at 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non insulin-dependent diabetes mellitus mice model. Compounds 2 and 3 showed robust in vitro and in vivo efficacy, and could be considered as promising multitarget antidiabetic drug candidates. This is the first report of a single molecule with these four polypharmacological target action.

Subject Areas

Diabetes; GPR40; AKRB1; PPARγ; GLUT-4

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