Pharmacological profiles of a novel protein tyrosine phosphatase 1B inhibitor, JTT‐551

Fukuda, Sumiaki; Ohta, Takeshi; Sakata, Shohei; Morinaga, Hisayo; Ito, Makoto; Nakagawa, Yuichi; Tanaka, Masaru; Matsushita, Mutsuyoshi

doi:10.1111/j.1463-1326.2009.01162.x

Cited by 57 publications

(44 citation statements)

References 38 publications

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“…The overexpression of PTP1B in muscle has been proposed to cause insulin resistance (21). Hepatic deletion and PTP1B inhibitors were shown to improve insulin resistance and reduce plasma glucose and TG levels in diabetic mice (14,22). The plasma concentrations of KY201 in OVX rats were compatible with PTP1B inhibitory concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…PTP1B is known as a nonreceptor type tyrosine phosphatase and negatively regulates insu lin and leptin signaling (11,12). The genetic deletion or pharmacological intervention of PTP1B is known to have antidiabetic and antiobesity effects by amplifying insulin and leptin signaling, respectively (13,14). KY 201 was previously reported to reduce plasma glucose and triglyceride (TG) levels more effectively than rosi glitazone in KKA y mice, even though both compounds have similar human PPARg agonistic activities in COS1 cells (10), which suggests the involvement of PTP1B inhibition in its insulinsensitizing effects.…”

Section: Introductionmentioning

confidence: 99%

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Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

et al. 2014

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Abstract. The pharmacological profile of (S)7(2{2[(E)2cyclopentylvinyl]5methyloxazol 4yl}ethoxy)2[(2E,4E)hexadienoyl]1,2,3,4tetrahydroisoquinoline3carboxylic acid (KY201), a peroxisome proliferatoractivated receptor (PPAR) g agonist, was compared with that of rosiglitazone in ovariectomized rats. The serum triglyceride and nonesterified fatty acid reducing effects of KY201 at 3 and 10 mg/kg per day for 6 weeks were similar to those of rosiglitazone despite its weaker PPARg agonistic activity. KY201 had no effects on body weight gain, blood volume, or heart and adipose weights, while rosiglitazone at 10 mg/kg per day increased them. KY201 had few effects on bone mineral density (BMD) or fat in marrow (FM), whereas rosiglitazone strongly decreased BMD and increased FM. The PPARγ agonistic activity of KY201 was weaker than that of rosiglitazone in ST2 cells, and KY201 reduced osteoblast differentiation and increased adipocyte differentiation less potently than rosiglitazone in rat bone marrowderived mesenchymal stem cells. KY201, but not rosiglitazone inhibited protein tyrosine phosphatase 1B (PTP1B) and increased phosphorylation of the insulin receptor in HepG2 cells. These results suggest that the hypolipidemic effects of KY201 are similar to those of rosiglitazone, but with less adverse effects, due to the combination of PPARg partial activation and PTP1B inhibition. KY201 would be useful for treatments of diabetic patients at high risk of osteoporosis, cardiovascular disease, and/or obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

et al. 2014

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“…Ito et al reported the antiobesity effects of JTT-551, which was developed as a novel PTP1B inhibitor [85,19]. The single administration of JTT-551 and leptin enhanced STAT3 phosphorylation in the hypothalamus of DIO mice, and the food intake resulted in a significant reduction as compared with that in the control group.…”

Section: Protein Tyrosine Phosphatase 1b Inhibitormentioning

confidence: 99%

Usefulness of Obese Animal Models in Antiobesity Drug Development

Ohta¹,

Murai²,

Yamada³

2017

Adiposity - Omics and Molecular Understanding

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“…При пероральном введении JTT-551 у мышей линии ob/ob с генетически обусловленным ожирением и линии db/db с СД улучшался метабо-лизм глюкозы, предположительно благодаря усиле-нию инсулиновой сигнализации [57]. При хрониче-ском введении JTT-551 у мышей с ожирением, ин-дуцированным высококалорийной диетой, снижал-ся вес и нормализовался метаболизм липидов и глю-козы [58].…”

Section: активация и потенцирование инсулиновой сигна-лизации улучшеunclassified

Promising pharmacological targets for the treatment of the diseases associated with the impaired insulin receptor signaling pathway

Gorbunov

Brigadirova

Качаева

et al. 2015

Probl Endokrinol (Mosk)

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ОБЗОРЫСахарный диабет (СД) занимает одно из первых мест в мире среди наиболее распространенных хро-нических заболеваний. В ряд социально значимых заболеваний СД ставят такие его особенности, как большая частота встречаемости, высокий риск ин-валидизации и смертности больных. В 2013 г., по данным Международной диабетической федерации, численность больных СД в мире составила 386 млн человек. Учитывая темпы распространения заболе-вания, согласно прогнозам экспертов ВОЗ, число пациентов с диагнозом СД достигнет к 2035 г. 592 млн человек в основном за счет больных СД 2-го типа (СД2) [1]. По данным Минздрава России, уро-вень инвалидизации по причине СД составляет 2,1 случая на 100 тыс. населения [2].СД представляет собой гетерогенную группу ме-таболических расстройств, которые характеризуют-ся общим симптомом -хронической гиперглике-мией, а также абсолютным или относительным де-фицитом продукции инсулина, либо его действия [3]. СД 1-го типа возникает из-за недостаточной продукции инсулина вследствие потери функцио- Diabetes mellitus (DM) is one of the most widespread chronic diseases in the world. In DM type 2, peripheral tissues demonstrate strong resistance to endogenous insulin (insulin resistance) which is caused by impaired ability of the hormone to stimulate glucose uptake in target cells (muscle, adipose or brain tissue, liver, etc.) and to reduce blood glucose level. Research data suggest that all mentioned reasons are most likely to be based on a disruption of signal transduction from insulin receptor (IR) into insulin-dependent intracellular signaling cascades. Contemporary DM treatment strategy is aimed at the maintenance of optimal blood glucose level by improving insulin production and increasing insulin sensitivity of tissue as well as prevention of macro-and microvascular complications and decrease of their intensity. At the same time, the search for new targets for creation of innovative anti-diabetic compounds can be considered a promising task due to the optimization of existing approaches and development of the novel ones taking into account results of the latest research into DM etiology and pathogenesis. A special position among possible targets is occupied by insulin receptor (IR) and IR-associated signaling pathways. Belonging to tyrosine kinase receptor family, IR has been actively studied during the last decades. This review considers in particular the IR structure and functioning of receptor-associated signaling pathways. The paper contains data on novel ligand-mimetics and IR sensitizers as well as other molecules, which affect different components of IR-associated signaling pathways, thus exerting significant antidiabetic effect. Action of these compounds is aimed at improvement of basic metabolic disorders resulting in hyperglycemia and is mainly carried out due to the following effects: activation and potentiation of insulin signaling, increase of insulin sensitivity of peripheral tissues; recovery of insulin secretion physiological mechanisms; reduction of glucose production in liver.

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Pharmacological profiles of a novel protein tyrosine phosphatase 1B inhibitor, JTT‐551

Abstract: JTT-551, a newly developed PTP1B inhibitor, improves glucose metabolism by enhancement of insulin signalling and could be useful in the treatment of type 2 diabetes mellitus.

Cited by 57 publications

References 38 publications

Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

Usefulness of Obese Animal Models in Antiobesity Drug Development

Promising pharmacological targets for the treatment of the diseases associated with the impaired insulin receptor signaling pathway

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