Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity

Kameda, Minoru; Kobayashi, Kensuke; Ito, Hirokatsu; Miyazoe, Hiroshi; Tsujino, Toshiaki; Nakama, Chisato; Kawamoto, Hiroshi; Ando, Makoto; Ito, Sayaka; Suzuki, Tadanao; Kanno, Toshio; Tanaka, Takeshi; Tahara, Yoshio; Tani, Takeshi; Tanaka, Sachiko; Tokita, Shigeru; Sato, Nagaaki

doi:10.1016/j.bmcl.2009.05.069

Cited by 8 publications

(9 citation statements)

References 22 publications

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“…A 2,4‐diaminopyridine‐based Y 1 antagonist turned out to be a highly promising compound, as it was shown to inhibit food intake after intraperitoneal administration in rodents. In addition to being a potential PET tracer candidate, this Y 1 R antagonist is suitable for diagnostic approaches116, 117. Also for the Y 2 R a nonpeptidic antagonist has been developed.…”

Section: Yrs As Targets In Drug Developmentmentioning

confidence: 99%

Neuropeptide Y receptors: ligand binding and trafficking suggest novel approaches in drug development

Walther

Mörl

Beck‐Sickinger

2011

Journal of Peptide Science

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NPY, PYY and PP constitute the so-called NPY hormone family, which exert its biological functions in humans through YRs (Y₁, Y₂, Y₄ and Y₅). Systematic modulation of YR function became important as this multireceptor/multiligand system is known to mediate various essential physiological key functions and is involved in a variety of major human diseases such as epilepsy, obesity and cancer. As several YRs have been found to be overexpressed on different types of malignant tumors they emerge as promising target in modern drug development. Here, we summarize the current understanding of YRs function and the molecular mechanisms of ligand binding and trafficking. We further address recent advances in YR-based drug design, the development of promising future drug candidates and novel approaches in YR-targeted tumor diagnostics and therapy opportunities.

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Section: Yrs As Targets In Drug Developmentmentioning

confidence: 99%

Neuropeptide Y receptors: ligand binding and trafficking suggest novel approaches in drug development

Walther

Mörl

Beck‐Sickinger

2011

Journal of Peptide Science

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“…The Y1 receptor antagonist J-115814 inhibits feeding in lean C57BL/6 mice and in hyperphagic db/db mice, which lack leptin signaling, and in mice with diet-induced obesity (DIO) [20,21]. However, J-115814 potently interacts with the I Kr potassium channel [18], suggesting that it could have cardiovascular side effects. Another Y1 receptor antagonist, BMS-193885, attenuates both NPY-induced and spontaneous nocturnal feeding following intraperitoneal administration to rats [19].…”

Section: Neuropeptide Ymentioning

confidence: 99%

“…Several Y1 receptor antagonists have been administered to ro-dents, but most have associated safety concerns, and none have been tested in humans [18,19]. The Y1 receptor antagonist J-115814 inhibits feeding in lean C57BL/6 mice and in hyperphagic db/db mice, which lack leptin signaling, and in mice with diet-induced obesity (DIO) [20,21].…”

Section: Neuropeptide Ymentioning

confidence: 99%

Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

Greenwood

Bloom²,

Murphy

2011

Rev Diabet Stud

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■ AbstractIt is estimated that 347 million people worldwide have diabetes and that over 1.5 billion adults worldwide are overweight. Predictions suggest these rates are increasing. Diabetes is a common complication in overweight and obese subjects, and in 2004, an estimated 3.4 million people died from consequences of high blood sugar. Thus, there is great interest in revealing the physiological systems that regulate body weight and blood sugar. Several peptidergic systems within the central nervous system and the periphery regulate energy homeostasis. A number of these systems have been investigated as potential treatments for obesity and the metabolic syndrome. However, manipulation of peptidergic systems poses many problems. This review discusses the peptidergic systems currently attracting research interest for their clinical potential to treat obesity. We consider first neuropeptides in the brain, including the orexigenic neuropeptide Y and melanin-concentrating hormone, and anorectic factors such as the melanocortins, ciliary neurotrophic factor, and neuromedin U. We subsequently discuss the utility of targeting peripheral gut peptides, including pancreatic polypeptide, peptide YY, amylin, and the gastric hormone ghrelin. Also, we analyze the evidence that these factors or drugs based on them may be therapeutically useful, while considering the disadvantages of using such peptides in a clinical context.

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“…The effect of J‐115814 appeared to be specifically mediated by the Y1 receptor because intraperitoneal administration did not reduce NPY‐induced food intake in Y1 receptor deficient mice as it did in wild‐type and Y5 receptor deficient animals (Kanatani et al ., 2001). However, the potential clinical application of J‐115814 as an anti‐obesity compound is hampered by the finding that it has a potent interaction with the I kr potassium channel (Kameda et al ., 2009b), suggesting that it could have the undesirable side effect of cardiovascular toxicity (Fermini and Fossa, 2003).…”

mentioning

confidence: 99%

“…With the aim of eliminating the inhibitory interaction of J‐115814 at the I kr potassium channel, Kameda and colleagues generated a library of diaminopyridine class compounds with reduced molecular size and hydrophobicity. This work led to the identification of compound Y1‐718 (Kameda et al ., 2009b). In vitro investigation of Y1‐718 showed that it had potent antagonistic activity in a [ 35 S]GTPγS assay, was selective for Y1 over Y2, Y4 and Y5 receptors, and – unlike its predecessor, J‐115814 – had negligible activity at the I kr potassium channel.…”

mentioning

confidence: 99%

NPY receptors as potential targets for anti‐obesity drug development

Yulyaningsih

Zhang

Herzog

et al. 2011

British J Pharmacology

117

113

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The neuropeptide Y system has proven to be one of the most important regulators of feeding behaviour and energy homeostasis, thus presenting great potential as a therapeutic target for the treatment of disorders such as obesity and at the other extreme, anorexia. Due to the initial lack of pharmacological tools that are active in vivo, functions of the different Y receptors have been mainly studied in knockout and transgenic mouse models. However, over recent years various Y receptor selective peptidic and non-peptidic agonists and antagonists have been developed and tested. Their therapeutic potential in relation to treating obesity and other disorders of energy homeostasis is discussed in this review. AbbreviationsARC, arcuate nucleus; d.d

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Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity

Cited by 8 publications

References 22 publications

Neuropeptide Y receptors: ligand binding and trafficking suggest novel approaches in drug development

Neuropeptide Y receptors: ligand binding and trafficking suggest novel approaches in drug development

Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

NPY receptors as potential targets for anti‐obesity drug development

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