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

Abstract

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 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.

Keywords: AKRB1; GPR40; PPARγ, GLUT-4; diabetes.

Figure 1

Drug design of multitarget compounds 1–5, which were designed from pharmacophore extraction and reorganization from known modulators of four targets: GPR40, PPARγ, GLUT-4, and AKR1B1.

Scheme 1

Synthesis of compounds 1–5.

Figure 2

(A) Effect of compounds 2 and 3 on expression level of PPARγ; (B) Effect of compounds on expression level of GLUT-4. Results are mean ± SEM (n = 6)/*** p < 0.001; ** p < 0.01; * p < 0.05 compared with control group.

Figure 3

(A) 3D binding model of compounds 1–3 into the ligand binding site of PPARγ. Compounds are presented as stick models: 1 (green), 2 (cyan) and 3 (magenta), and aminoacids as lines. Dashed line signifies polar interactions; (B) 2D interaction map of the most active compound 3 and PPARγ.

Figure 4

(A) 3D binding model of compounds 1–3 into the allosteric ligand binding site of GPR40. Compounds are presented as stick models: 1 (green), 2 (cyan) and 3 (magenta). (B) 2D interaction map of the most active compound 1 and GPR40.

Figure 5

(A) 3D binding model of compounds 1–3 into the active site of Aldose reductase (AKR1B1). Compounds are presented as stick models: 1 (green), 2 (cyan) and 3 (magenta); (B) 2D interaction map of the second most active compound 2 and AKR1B1.

Figure 6

Effect of a single dose (100 mg/kg) of compounds 1–3 and glibenclamide (5 mg/kg) in STZ-NA induced diabetes mice model (intragastric, n = 6). * p < 0.05 versus Tween 80 (10%) group.