Structure-based design of protein tyrosine phosphatase-1B inhibitors

Black, Emma; Breed, J.; Breeze, Alexander L.; Embrey, Kevin J.; Garcia, Robert; Gero, Thomas W.; Godfrey, Linda; Kenny, Peter W.; Morley, Andrew D.; Minshull, Claire A.; Pannifer, Andrew; Read, Jon; Rees, Amanda; Russell, Daniel; Toader, Dorin; Tucker, J.A.

doi:10.1016/j.bmcl.2005.03.068

Cited by 70 publications

(63 citation statements)

References 16 publications

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“…Considering the clinical importance of obesity and diabetes, inhibitors of PT1B containing cyclic sulfamide scaffold represent valuable candidates for the development of useful drugs. 105 …”

Section: B Sulfamides As Protein Tyrosine Phosphatase Inhibitorsmentioning

confidence: 97%

“…Recently Black et al 105 have reported a small series of N-aryl substituted 1,2,5-thiadiazolidin-3-one 1,1-dioxides of type 53. One compound of this series has shown low micromolar inhibition of PT1B, which constitute interesting lead compound for further development.…”

Section: B Sulfamides As Protein Tyrosine Phosphatase Inhibitorsmentioning

confidence: 99%

“…[101][102][103][104] Numerous inhibitors have been described and developed by both academia and pharmaceutical companies over the last few years. 105 Astra Zeneca 106 and Novartis 107 have claimed that 1,2,5-thiadiazolidin-3-one 1,1-dioxides scaffold can be used in the design of selective and potent inhibitors of PTP1B, of types 51 and 52. They have introduced a large series of N-benzyl (or N-aryl or N-heterocyclic) 1,2,5-thiadiazolidin-3-one 1,1-dioxides substituted in various ways on the aromatic ring.…”

Section: B Sulfamides As Protein Tyrosine Phosphatase Inhibitorsmentioning

confidence: 99%

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Therapeutic potential of sulfamides as enzyme inhibitors

Winum¹,

Scozzafava²,

Montéro³

et al. 2006

Med. Res. Rev.

178

107

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Sulfamide, a quite simple molecule incorporating the sulfonamide functionality, widely used by medicinal chemists for the design of a host of biologically active derivatives with pharmacological applications, may give rise to at least five types of derivatives, by substituting one to four hydrogen atoms present in it, which show specific biological activities. Recently, some of these compounds started to be exploited for the design of many types of therapeutic agents. Among the enzymes for which sulfamide-based inhibitors were designed, are the carbonic anhydrases (CAs), a large number of proteases belonging to the aspartic protease (HIV-1 protease, gamma-secretase), serine protease (elastase, chymase, tryptase, and thrombin among others), and metalloprotease (carboxypeptidase A (CPA) and matrix metalloproteinases (MMP)) families. Some steroid sulfatase (STS) and protein tyrosine phosphatase inhibitors belonging to the sulfamide class of derivatives have also been reported. In all these compounds, many of which show low nanomolar affinity for the target enzymes for which they have been designed, the free or substituted sulfamide moiety plays important roles for the binding of the inhibitor to the active site cavity, either by directly coordinating to a metal ion found in some metalloenzymes (CAs, CPA, STS), usually by means of one of the nitrogen atoms present in the sulfamide motif, or as in the case of the cyclic sulfamides acting as HIV protease inhibitors, interacting with the catalytically critical aspartic acid residues of the active site by means of an oxygen atom belonging to the HN-SO2-NH motif, which substitutes a catalytically essential water molecule. In other cases, the sulfamide moiety is important for inducing desired physico-chemical properties to the drug-like compounds incorporating it, such as enhanced water solubility, better bioavailability, etc., because of the intrinsic properties of this highly polarized moiety when attached to an organic scaffold. This interesting motif is thus of great value for the design of pharmacological agents with a lot of applications.

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Section: B Sulfamides As Protein Tyrosine Phosphatase Inhibitorsmentioning

confidence: 97%

Section: B Sulfamides As Protein Tyrosine Phosphatase Inhibitorsmentioning

confidence: 99%

Section: B Sulfamides As Protein Tyrosine Phosphatase Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic potential of sulfamides as enzyme inhibitors

Winum¹,

Scozzafava²,

Montéro³

et al. 2006

Med. Res. Rev.

178

107

View full text Add to dashboard Cite

show abstract

“…E-mail: m_monajjemi@yahoo.com antiulcerative, anti-hypertensive, antiviral, antifungal, antitumor and antihistaminic agents, and antihelminthic agents in veterinary medicine (Spasov et al, 1999). Benzimidazole derivatives have found the appreciation in diverse therapeutic areas including antimicrobial activity Wu et al, 2003;Mollaamin et al, 2008;Ozden et al, 2005;Sztanke et al, 2006), the activity against several viruses such as HIV (Porcari et al ., 1998;Samia et al, 2006), antiallergic (Kilcig and Altanlar, 2006;Nakano et al, 1999), antioxidant, antihistaminic (Vijayakumar and Jafar Ahamed, 2010), antitubercular (Yadav and Srivastava, 2011;Kuchkguzel et al, 2001), antiasthmatic (Souness et al, 2000), antidiabetic (Senten et al, 2003;Black et al, 2005), anticancer (Pal et al, 2011;Sun et al, 2011;Kruse et al,1989;Islam et al,1991;Ramla et al,2007), antitumor (Denny et al, 1990 ;Tatsuta et al, 2005), antiulcer (Jung et al, 1993;Hazelton et al, 1995), antihelmentic (Karen, 2006), HIV-1 reverse transcriptase inhibitors (Gardiner et al, 2003), anticoagulant (Young et al, 2006), anti inflammatory (Fox et al, 2009), antibacterial (Rosowsky et al, 1997;Andrzejewska et al, 2004) , the series of biologically active benzimidazoles (AJafar et al,2009). Furthermore, these heterocycles are considered to be privileged structures by medicinal chemists.…”

Section: Introductionmentioning

confidence: 99%

NMR and NBO calculation of benzimidazoles and pyrimidines: Nano physical parameters investigation

Monajjemi¹

2012

Int. J. Phys. Sci.

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Six theoretical methods were used for the calculation of physical parameters for derivatives of pyrimidines and benzimidazols. We used Gaussian 98 at NMR and NBO calculations by using HF method with 6-31G, 6-31G* and 6-31+G basis set and B3LYP, BLYP and B3PW91 methods with 6-31G basis set. Chemical shift was drawn curve for all of the atoms in each molecule. The thermo chemical parameters including thermal energy(ΔΕ), atomic charges, chemical shift anisotropy(δ), asymmetry parameter(η), chemical shift anisotropy(∆σ), dipole orientation, isotropic, anisotropic, NMR determinant and distance matrix compounds. Also the natural bond orbital (NBO) analysis has been performed which seem informative to show some important atomic and structural features.

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“…A more recent example in PTP1B inhibitor development involves a rational design effort that resulted in the discovery of the 1,2,5-thiadiazolidin-3-one-1,1-dioxide group as a novel mimic the phosphoryl moiety of pTyr [50]. When incorporated into a di-peptide structure, the isothiazolidinone containing inhibitor V has a K i of 0.19 μM [51].…”

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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Structure-based design of protein tyrosine phosphatase-1B inhibitors

Cited by 70 publications

References 16 publications

Therapeutic potential of sulfamides as enzyme inhibitors

Therapeutic potential of sulfamides as enzyme inhibitors

NMR and NBO calculation of benzimidazoles and pyrimidines: Nano physical parameters investigation

Targeting PTPs with small molecule inhibitors in cancer treatment

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