Discovery of potent, selective and orally bioavailable triaryl-sulfonamide based PTP1B inhibitors

Patel, Dipam; Jain, Mukul; Shah, Shailesh R.; Bahekar, Rajesh; Jadav, Pradip; Joharapurkar, Amit; Dhanesha, Nirav; Shaikh, Mubeen; Sairam, Kalapatapu V.V.M.; Kapadnis, Prashant B.

doi:10.1016/j.bmcl.2011.11.122

Cited by 46 publications

(23 citation statements)

References 28 publications

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“…In 2012, a series of triaryl-sulfonamide derivatives are reported by Patel group as potent and selective PTP1B inhibitors. 44 Most potent compound 31 showed excellent selectivity (96-fold) toward PTP1B over TCPTP (Table 4). Docking results showed that compound 31 docks very well into both the A and B sites.…”

Section: Exploration Of Arg47 Asp48 and Lys41mentioning

confidence: 97%

The design strategy of selective PTP1B inhibitors over TCPTP

Wang

Shi

2016

Bioorganic & Medicinal Chemistry

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Section: Exploration Of Arg47 Asp48 and Lys41mentioning

confidence: 97%

The design strategy of selective PTP1B inhibitors over TCPTP

Wang

Shi

2016

Bioorganic & Medicinal Chemistry

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“…Interestingly, PTPN1 is associated with insulin regulation, T2DM, and inflammation (Kenner et al, 1996;Zabolotny et al, 2008) therefore, PTPN1 inhibitors may be potential therapeutic targets for T2DM (Patel et al, 2012). Similarly, integration of gene expression data from multiple studies elucidated a transcriptional signature in blood characteristic of PD and T2DM.…”

Section: A Network View Of T2dm and Neurodegenerationmentioning

confidence: 99%

Splice Variant Biomarkers for Parkinson's Disease

Potashkin¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATEMay PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERRosalind Franklin U. Medicine & Science 3333 Green Bay Rd. North Chicago, IL 60064-3037 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTRecently we identified splice variants in whole blood than can distinguish early stage Parkinson's disease (PD) patients from healthy and neurodegenerative controls. The proposed studies will test the hypothesis that the biomarkers will be useful for identifying individuals at risk for PD and for identifying signaling pathways that are disrupted in PD. We are testing the expression of the biomarkers in RNA prepared from whole blood of hyposmic participants in the Parkinson's Associated Risk Study (PARS) (Technical Objective 1.0). In order to establish a model for testing the function of the biomarkers, we are determining whether their expression is altered in human olfactory neurosphere-derived (hONS) cells derived from idiopathic PD patients and healthy controls (Technical Objective 2.0). To determine the signaling pathways affected in PD and identify additional biomarkers, we are using network analysis (Technical Objective 3.0). During year 1, RNA and cDNA was prepared from PARS samples from Year 0 (baseline) and Year 2. Quantitative polymerase chain reactions were initiated for two of the biomarkers (APP, HNF4α). Expression of the biomarkers was tested in hONS. We also developed network approaches to reveal the common molecular pathways involved with PD and type 2 diabetes (T2DM). Using these networks, we identified APP, HNF4A and SOD2 mRNAs as blood biomarkers predictive of early stage PD. In addition, we determined that HNF4A mRNA may be a progression marker in blood for PD. SUBJECT TERMSParkinson's disease, biomarkers, neurodegeneration, network and pathway analysis 12-15Santiago 16-23Sei...

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“…Then, the unsymmetric thioureas (5) prepared from the reaction of methyl isothiocyanate and various amines, were reacted with 4-chloroacetoanilides to deliver the desired 2-iminothiazole derivatives (6).…”

Section: 9mentioning

confidence: 99%

“…Among them, further structurally optimized Ertiprotafib was submitted to a clinical trial but was discontinued in the second phase ( Figure 1). 6,7 In this regard, our group made much effort to find out new chemical scaffolds with inhibitory activities against PTP1B without mimicking phosphotyrosine. In search of new hit compounds for drug discovery, utilizing chemical library based on privileged structures gives some benefits in terms of proved drug-like properties such as inherent low toxicity, good pharmacokinetic profiles, and easiness of synthesis.…”

mentioning

confidence: 99%

Privileged Structure-based Discovery of Novel 2-Iminothiazoles as Protein Tyrosine Phosphatase 1B Inhibitors

Ahn¹,

Lee²,

Shin

2013

Bulletin of the Korean Chemical Society

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Protein tyrosine phosphatase 1B (PTP1B) is a wellestablished metabolic regulator and a member of PTP superfamily that catalyzes protein tyrosine dephosphorylation. Many scientific evidences have shown that PTP1B plays a broad role in the regulation of body metabolism, particularly in cancer development.1-3 In the insulin signaling pathway, PTP1B can be involved in dephosphorylation of activated insulin receptor (IR) or insulin receptor substrates (IRS). PTP1B can also bind and dephosphorylate JAK2, which activates STAT3 responsible for downstream functions such as food uptake and energy homeostasis in the leptin pathway. Elevated leptin sensitivity by activated or phosphorylated JAK2 in the PTP1B −/− mice is related to increased energy expenditure, which eventually results in homeostatic regulation of the blood glucose level and body weight. 4An effective control of the phosphatase may provide a useful tool in treatment of diseases such as type 2 diabetes and obesity. However, there is no reported PTP1B inhibitor that has passed through the sequence of clinical tests for treatment of the diseases, although many inhibitors showed potency in vitro assays. In general, mimicking phosphotyrosine has been the starting point of development of active site-directed PTPase inhibitors.5 However, the majority of the active site directed PTP1B inhibitors have shown a low level of cellular uptake because they usually contain the highly charged moieties such as phosphate and carboxylic acid. Recently, potent PTP1B inhibitors were obtained from high-throughput screening of chemical libraries. Among them, further structurally optimized Ertiprotafib was submitted to a clinical trial but was discontinued in the second phase (Figure 1). 6,7In this regard, our group made much effort to find out new chemical scaffolds with inhibitory activities against PTP1B without mimicking phosphotyrosine. In search of new hit compounds for drug discovery, utilizing chemical library based on privileged structures gives some benefits in terms of proved drug-like properties such as inherent low toxicity, good pharmacokinetic profiles, and easiness of synthesis. 8,9Therefore, structurally diversified chemical set was selected from our proprietary privileged structure-based chemical library, which was designed and constructed for drug discovery. Herein, we communicate discovery of novel 2-iminothiazole compounds for PTP1B as a potential anti-diabetic.Initially, 182 compounds were screened for PTB1B inhibitory activities at 100 μM using fluorescence polarization (FP)-based PTP1B assays to give 20 compounds which showed over 50% inhibition. Then, selected compounds were screened again at 20 μM to give two hit compounds with 22% and 99% inhibitory activities, respectively. These two compounds share common structure, N-cyclohexyl-2-(3-methyl-2-(phenylimino)-2,3-dihydrothiazol-4-yl)acetamide (Figure 2).With initial hit compounds in hand, we designed new chemical library focused on 2-aryliminothiazole moiety. Synthesis of the library was carried out followi...

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Discovery of potent, selective and orally bioavailable triaryl-sulfonamide based PTP1B inhibitors

Cited by 46 publications

References 28 publications

The design strategy of selective PTP1B inhibitors over TCPTP

The design strategy of selective PTP1B inhibitors over TCPTP

Splice Variant Biomarkers for Parkinson's Disease

Privileged Structure-based Discovery of Novel 2-Iminothiazoles as Protein Tyrosine Phosphatase 1B Inhibitors

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