Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: Synthesis and structure–activity relationships of a peptide scaffold

Yue, Eddy W.; Wayland, Brian; Douty, Brent; Crawley, Matthew L.; McLaughlin, Erin; Takvorian, Amy; Wasserman, Zelda R.; Bower, Michael J.; Wei, Min; Li, Yanlong; Paul, Jean-Claude; Gonneville, Lucie; Wynn, Richard; Burn, Timothy C.; Liu, Phillip C.C.; Combs, Andrew P.

doi:10.1016/j.bmc.2006.05.032

Cited by 48 publications

(27 citation statements)

References 36 publications

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“…The mechanism of pyrimidotriazine indicated that in presence of Dithiothreitol (DTT) and absence of oxygen, the structurally related pyrimidotriazine rapidly and quantitatively underwent reduction to the corresponding dihydro derivative which was reversible in the presence of atmospheric oxygen. Among the series compound (118)(119)(120)(121) showed inhibitory activity against PTP 1B in micromolar concentration indicating hydrophobic benzylic side chains (e.g. 118-121) were favored on the piperazine ring (Table XIX).…”

Section: K Acetophenonesmentioning

confidence: 99%

“…This compound (119) is rapidly and extensively distributed and achieved systemic exposure (C max ) approximated the measured IC 50 against PTP 1B in vitro (Table XX). It has a favorable t 1/2 (118)(119)(120)(121) and excellent oral bioavailability. The large steady state volume of distribution (V ss ) of (119) is approximately six times the total body water volume of the animal, suggesting deep tissue and cell penetration.…”

Section: K Acetophenonesmentioning

confidence: 99%

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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

107

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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.

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Section: K Acetophenonesmentioning

confidence: 99%

Section: K Acetophenonesmentioning

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

107

View full text Add to dashboard Cite

show abstract

“…107 In addition, the IZD ring has to be saturated, because the unsaturated molecule displayed a 30-fold decrease in potency (60 versus 65). 109 With regard to cell permeability, only a few compounds, such as 61 and 62, were able to increase the phosphorylation level of IR in a dose-dependent manner. 110 And this class of compounds displayed poor selectivity over Tc-PTP, for example, with compound 66 having an identical IC 50 value against both PTP1B and Tc-PTP.…”

Section: Imidesmentioning

confidence: 99%

“…Incyte has published a series of molecules with the IZD group incorporated on various scaffolds, such as peptides, sulfonamides, and heterocycles. [107][108][109][110][111][112] Representative compounds from each class are summarized in Figure 6.7 (compounds 59-63). Their IC 50 values for PTP1B range from 10 to 180 nM, suggesting that IZD is an effective p-Tyr mimetic in inhibiting PTP1B.…”

Section: Imidesmentioning

confidence: 99%

Chapter 6. Recent Advances in PTP1B Inhibitor Development for the Treatment of Type 2 Diabetes and Obesity

He¹,

Zeng²,

He³

et al. 2012

Drug Discovery

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“…When incorporated into a di-peptide structure, the isothiazolidinone containing inhibitor V has a K i of 0.19 μM [51]. Using the isothiazolidinone group as the pTyr mimetic, a peptide-based inhibitor VI was synthesized which showed an IC 50 of 40 nM, demonstrating the utility of the isothiazolidinone to serve as a highly efficacious pTyr mimetic [52]. To improve the cell permeability and oral bioavailability, a series of nonpeptide based inhibitors using the same isothiazolidinone group as the pTyr mimetic were synthesized.…”

Section: Ptp1bmentioning

confidence: 99%

Targeting PTPs with small molecule inhibitors in cancer treatment

Jiang

Zhang

2008

Cancer Metastasis Rev

113

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Protein tyrosine phosphorylation plays a major role in cellular signaling. The level of tyrosine phosphorylation is controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Disturbance of the normal balance between PTK and PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. A number of PTPs have been implicated in oncogenesis and tumor progression and therefore are potential drug targets for cancer chemotherapy. These include PTP1B, which may augment signaling downstream of HER2/Neu; SHP2, which is the first oncogene in the PTP superfamily and is essential for growth factor-mediated signaling; the Cdc25 phosphatases, which are positive regulators of cell cycle progression; and the PRL phosphatases, which promote tumor metastases. As PTPs have emerged as drug targets for cancer, a number of strategies are currently been explored for the identification of various classes of PTP inhibitors. These efforts have resulted many potent, and in some cases selective, inhibitors for PTP1B, SHP2, Cdc25 and PRL phosphatases. Structural information derived from these compounds serves as a solid foundation upon which novel anti-cancer agents targeted to these PTPs can be developed.

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Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: Synthesis and structure–activity relationships of a peptide scaffold

Cited by 48 publications

References 36 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

Chapter 6. Recent Advances in PTP1B Inhibitor Development for the Treatment of Type 2 Diabetes and Obesity

Targeting PTPs with small molecule inhibitors in cancer treatment

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