Structure‐Based Optimization of Benzoic Acids as Inhibitors of Protein Tyrosine Phosphatase 1B and Low Molecular Weight Protein Tyrosine Phosphatase

Maccari, Rosanna; Ottanà, Rosaria; Paoli, Paolo; Manao, Giampaolo; Camici, Giovanni G.; Laggner, Christian; Langer, Thierry

doi:10.1002/cmdc.200800427

Cited by 30 publications

(31 citation statements)

References 42 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Molecular docking studies also indicated that these compounds interact with amino acid residues involved in the affinity and selectivity of inhibitors toward this enzyme. 104 Bhattarai et al identified TZD scaffolds as PTP 1B inhibitors by means of a computeraided drug design protocol involving virtual screening. A series of benzylidene-2, 4-thiazolidinedione derivatives with substitutions on the phenyl ring at the ortho or para positions of the thiazolidinedione (TZD) group were reported with IC 50 values in a low micromolar range.…”

Section: A Thiazolidinedionesmentioning

confidence: 99%

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

Thareja

Aggarwal

Bhardwaj

et al. 2010

Medicinal Research Reviews

106

View full text Add to dashboard Cite

Diabetes mellitus is a systemic disease responsible for morbidity in the western world and is gradually becoming prevalent in developing countries too. The prevalence of diabetes is rapidly increasing in industrialized countries and type 2 diabetes accounts for 90% of the disease. Insulin resistance is a major pathophysiological factor in the development of type 2 diabetes, occurring mainly in muscle, adipose tissues, and liver leading to reduced glucose uptake and utilization and increased glucose production. The prevalence and rising incidence of diabetes emphasized the need to explore new molecular targets and strategies to develop novel antihyperglycemic agents. Protein Tyrosine Phosphatase 1B (PTP 1B) has recently emerged as a promising molecular level legitimate therapeutic target in the effective management of type 2 diabetes. PTP 1B, a cytosolic nonreceptor PTPase, has been implicated as a negative regulator of insulin signal transduction. Therefore, PTP 1B inhibitors would increase insulin sensitivity by blocking the PTP 1B-mediated negative insulin signaling pathway and might be an attractive target for type 2 diabetes mellitus and obesity. With X-ray crystallography and NMR-based fragment screening, the binding interactions of several classes of inhibitors have been elucidated, which could help the design of future PTP 1B inhibitors. The drug discovery research in PTP 1B is a challenging area to work with and many pharmaceutical organizations and academic research laboratories are focusing their research toward the development of potential PTP 1B inhibitors which would prove to be a milestone for the management of diabetes.

show abstract

Section: A Thiazolidinedionesmentioning

confidence: 99%

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

Thareja

Aggarwal

Bhardwaj

et al. 2010

Medicinal Research Reviews

106

View full text Add to dashboard Cite

show abstract

“…The synthesis of inhibitors 7aee and 8aee was carried out according to a previously reported procedure which is depicted in Scheme 1 [54,55].…”

Section: Chemistrymentioning

confidence: 99%

“…Interesting results have been achieved obtaining potent PTP inhibitors endowed with IC 50 values at submicromolar levels. They have been shown to act as competitive and reversible PTP inhibitors with significant selectivity for PTP1B and the IF1 isoform of LMW-PTP [53,54].…”

Section: Introductionmentioning

confidence: 99%

“…In fact, the insertion of a 2-phenylimino moiety in the 4-thiazolidinone scaffold provides 4-[(5-arylidene-2-phenylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids (2, Fig. 1) which have proven to be interesting inhibitors of both PTP1B and the IF1 isoform of LMW-PTP as well as being generally more active than the 2-oxo analogues 1 [54,55].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Ottanà

Maccari

Amuso

et al. 2012

European Journal of Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…On the other hand, the identified competitive inhibitor 2 was active towards all tested PTPs, and similar 2,4-thiazolidinones have been recently described as PTP inhibitors. [21] According to our results, compound 2 is an unselective and competitive PTP inhibitor-K I values have been determined for the four PTPs (Scheme 1). Moreover, the nonselectivity of 2 is in agreement with the high homology of the active sites of PTPs.…”

Section: Resultsmentioning

confidence: 99%

Dynamic Substrate Enhancement for the Identification of Specific, Second‐Site‐Binding Fragments Targeting a Set of Protein Tyrosine Phosphatases

2011

View full text Add to dashboard Cite

Protein tyrosine phosphatases (PTPs) are key regulators in living systems and thus are attractive drug targets. The development of potent, selective PTP inhibitors has been a difficult challenge mainly due to the high homology of the phosphotyrosine substrate pockets. Here, a strategy of dynamic substrate enhancement is described targeting the secondary binding sites of PTPs. By screening four different PTPs from bacterial (MptpA) and human origin (PTP1B, HePtp, Shp2) with this assay, specific fragments were identified. One highly specific fragment that binds to the secondary site of Mycobacterium tuberculosis protein tyrosine phosphatase A (MptpA) was characterized in order to validate the assay concept. Finally by covalently linking the secondary fragment to a phosphotyrosine mimetic, a moderately active but highly specific inhibitor of MptpA was obtained.

show abstract

Structure‐Based Optimization of Benzoic Acids as Inhibitors of Protein Tyrosine Phosphatase 1B and Low Molecular Weight Protein Tyrosine Phosphatase

Cited by 30 publications

References 42 publications

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

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

Dynamic Substrate Enhancement for the Identification of Specific, Second‐Site‐Binding Fragments Targeting a Set of Protein Tyrosine Phosphatases

Contact Info

Product

Resources

About