New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells

Abstract

a b s t r a c tIn pursuing our research targeting the identification of potent inhibitors of PTP1B and LMW-PTP, we have identified new 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids endowed with interesting in vitro inhibitory profiles. Most compounds proved to be inhibitors of PTP1B and LMW-PTP isoform IF1. The tested inhibitors also showed selectivity towards PTP1B over the closely related TC-PTP. These compounds were found to activate the insulin-mediated signalling on mouse C2C12 skeletal muscle cells by increasing the phosphorylation levels of the insulin receptor and promoting cellular 2-deoxyglucose uptake.Interestingly, 4-{[5-(4-benzyloxybenzylidene)-2-(4-trifluoromethylphenylimino)-4-oxo-3-thiazolidinyl] methyl}benzoic acid (7d), the best in vitro inhibitor of PTP1B and the isoform IF1 of LMW-PTP, provided the highest activation level of the insulin receptor and was found to be endowed with an excellent insulinomimetic effect on the selected cells. This compound therefore represents an interesting lead compound for developing novel PTP1B and LMW-PTP inhibitors which could be achieved by improving both its pharmacological profile and its potentiating effects on insulin signalling.

The Discovery of a Novel and Selective Inhibitor of PTP1B Over TCPTP: 3D QSAR Pharmacophore Modeling, Virtual Screening, Synthesis, and Biological Evaluation

“…According to the guidelines and experiences for quantitative 3D QSAR model generation in Discovery studio program with hypogen requirement , we selected a set of 56 compounds that are reported to be inhibitors of PTP‐1B. Of these 56 compounds, 22 compounds (Figure ) were taken as training set and the rest of the 34 compounds (Figure S1) as test set. The experimental activity of these 56 compounds is shown in Table S1.…”

“…The same methods and guidelines were applied to generate pharmacophore model for TCPTP inhibitors. Sixteen compounds (Figure ) of TCPTP inhibitors were taken as training set and the other 22 compounds (Figure S2) as test set. The experimental activity of the training set and the test set compounds is shown in Table S2.…”

An investigation on 4-thiazolidinone derivatives as dual inhibitors of aldose reductase and protein tyrosine phosphatase 1B, in the search for potential agents for the treatment of type 2 diabetes mellitus and its complications

“…22 Herein, starting from our structure-activity relationship (SAR) studies performed on numerous 4-thiazolidinone derivatives active as AR or PTP1B inhibitors, [23][24][25][26][27][28][29][30][31][32][33][34][35][36] we report the evaluation of a series of (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)acetic acids and 2-oxo/phenylimino analogues (1-17) (Table 1) as dual AR/PTP1B inhibitors. Our previous SAR studies [23][24][25][26][27][28][29][30][31][32][33][34][35][36] highlighted that the pharmacophores of these inhibitors of AR and PTP1B share several structural features that make possible the design of potential dual inhibitors: i) a polar portion, including an acidic moiety or H-bond acceptor groups, which can strongly interact with the positively charged region of the catalytic sites of both enzymes; ii) a lipophilic moiety, generally containing an aromatic system, which can bind hydrophobic amino acid residues lining the lipophilic specificity pocket of AR (such as Trp111, Thr113, Phe122, Ala299, Leu300, Ser302) and the phosphate-binding secondary non-catalytic pocket of PTP1B (such as Arg24, Ala27, Arg254, Met258, Gly259). It is worth pointing out that the 4-thiazolidinone scaffold appears to be capable to maintain a proper orientation of these crucial portions to effectively bind each enzyme and, at the same time, can establish useful interactions which may contribute to stabilize the complex enzyme/inhibitor.…”

“…It is worth pointing out that the 4-thiazolidinone scaffold appears to be capable to maintain a proper orientation of these crucial portions to effectively bind each enzyme and, at the same time, can establish useful interactions which may contribute to stabilize the complex enzyme/inhibitor. [23][24][25][26][27][28][29][30][31][32][33][34][35][36] Therefore, starting from a "knowledge-based" approach, we merged pharmacophoric elements of inhibitors directed to each of the selected enzymes, maintaining the shared 4-thiazolidinone core. In particular, we decided to insert on the N-3 of the thiazolidinone scaffold an acetic chain, which had been shown to be critical to achieve strong AR inhibition [23][24][25][26][27][28][29][30] and might also be suitable to interact with the positively charged catalytic centre of PTP1B.…”

Validation of Formylchromane Derivatives as Protein Tyrosine Phosphatase 1B Inhibitors by Pharmacophore Modeling, Atom‐Based 3D‐QSAR and Docking Studies

“…The equilibrium established between these two processes regulates the physiological tyrosine phosphorylation levels in the body, thereby controlling the normal blood glucose stratum. It has been hypothesized that the over activity of enzyme PTP 1B could be a contributing factor for the development of insulin resistance and T2DM . Thus, PTP 1B inhibitors are of therapeutic interest because of their potential to block the cascade of events following insulin‐mediated receptor activation by suppressing dephosphorylation of the IR, thereby maintaining the receptor in an activated state and hence prolonging the insulin action.…”