Discovery and structure–activity relationships of novel sulfonamides as potent PTP1B inhibitors

Holmes, Christopher P.; Li, Xianfeng; Pan, Yijun; Xu, Chao; Bhandari, Ashok; Moody, Claire M.; Miguel, Joy A.; Ferla, Steven W.; Francisco, M. Nuria De; Frederick, Brian; Zhou, Siqun; Macher, Natalie; Jang, Larry; Irvine, Jennifer D.; Grove, Jeffrey

doi:10.1016/j.bmcl.2005.06.061

Cited by 34 publications

(8 citation statements)

References 42 publications

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“…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.…”

Section: Methodsmentioning

confidence: 99%

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

Jin

Wang

et al. 2014

Chem Biol Drug Des

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Given the special role of insulin and leptin signaling in various biological responses, protein-tyrosine phosphatase-1B (PTP1B) was regarded as a novel therapeutic target for treating type 2 diabetes and obesity. However, owing to the highly conserved (sequence identity of about 74%) in active pocket, targeting PTP1B for drug discovery is a great challenge. In this study, we employed the software package Discovery Studio to develop 3D QSAR pharmacophore models for PTP1B and TCPTP inhibitors. It was further validated by three methods (cost analysis, test set prediction, and Fisher's test) to show that the models can be used to predict the biological activities of compounds without costly and time-consuming synthesis. The criteria for virtual screening were also validated by testing the selective PTP1B inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed a novel and selective inhibitor of PTP1B over TCPTP. After that, a most likely binding mode was proposed. Thus, the findings reported here may provide a new strategy in discovering selective PTP1B inhibitors.

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Section: Methodsmentioning

confidence: 99%

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

Jin

Wang

et al. 2014

Chem Biol Drug Des

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“…Compound (21) emerged as the most potent compound of the series with IC 50 and K i at submicromolar level. 116 Holmes et al further reported a series of triaryl sulfonamide-based PTP 1B inhibitors in which a DFMP group of a potent lead has been replaced by potential bioisosteric replacements. Although most of monocharged bioisosteres are not as active as those of dianionic pTyr mimetics, o-bromophenoxyacetic acid appears to compare favorably with dianionic o-carboxymethyl salicylic acid and 2-(oxaylamino) benzoic acid.…”

Section: B Phosphorus-containing Phosphotyrosyl Mimeticsmentioning

confidence: 97%

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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“…PTP B1 knockout mice display enhanced insulin sensitivity and resistance to diet induced obesity. Therefore novel PTP 1B inhibitors could be used to treat type 2 diabetes and obesity [39,40]. Fluorinated derivatives, benzylic a,a-difluorophosphonates, a,adifluorosulfonates and a,a-fluorocarboxylates, have been found to be potent inhibitors of PTP1B compared to non-fluorinated equivalents.…”

Section: Replacement With Difluoromethylenementioning

confidence: 99%

The role of fluorine in medicinal chemistry

Shah

Westwell

2007

Journal of Enzyme Inhibition and Medicinal Chemistry

607

392

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The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18 F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties.

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Discovery and structure–activity relationships of novel sulfonamides as potent PTP1B inhibitors

Cited by 34 publications

References 42 publications

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

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

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

The role of fluorine in medicinal chemistry

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