Novel orally active NPY Y5 receptor antagonists: Synthesis and structure–activity relationship of spiroindoline class compounds

Sakamoto, Toshihiro; Moriya, M.; Tsuge, Hiroyasu; Takahashi, Toshiyuki; Haga, Yuji; Nonoshita, Katsumasa; Okamoto, Osamu; Takahashi, Hirobumi; Sakuraba, Aya; Hirohashi, Tomoko; Shibata, Toshihiro; Kanno, Toshio; Itô, Junko; Iwaasa, Hisashi; Gomori, Akira; Ishihara, Akane; Fukuroda, Takahiro; Kanatani, Akio; Fukami, Tatsuki

doi:10.1016/j.bmc.2009.05.064

Cited by 11 publications

(5 citation statements)

References 36 publications

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“…Meanwhile, for analogues 44b and 44d , an alternate synthetic route was used. 1,4-Dinitro-1 H -imidazole was obtained by the nitration of 42 following a known general procedure . The treatment of 1,4-dinitroimidazole 46 with primary amines afforded the N 1-substituted 4-nitroimidazole 47 , followed by hydrogenation to provide 44b and 44d .…”

Section: Chemistrymentioning

confidence: 99%

“…1,4-Dinitro-1H-imidazole was obtained by the nitration of 42 following a known general procedure. 41 The treatment of 1,4-dinitroimidazole 46 with primary amines afforded the N1-substituted 4-nitroimidazole 47, followed by hydrogenation to provide 44b and 44d. Compounds 10a−d and 11a−d containing a scaffold of 6chloroquinazoline-2,4-diamine were synthesized as shown in Scheme 2.…”

Section: ■ Chemistrymentioning

confidence: 99%

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Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

et al. 2017

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Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2,4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors' selectivity, therapeutic potency, and pharmaceutical properties were optimized. One of the best compounds, 31 (CZh226), showed remarkable PAK4 selectivity (346-fold vs PAK1) and favorable kinase selectivity profile. Moreover, this compound potently inhibited the migration and invasion of A549 tumor cells by regulating the PAK4-directed downstream signaling pathways in vitro. Taken together, these data support the further development of 31 as a lead compound for PAK4-targeted anticancer drug discovery and as a valuable research probe for the further biological investigation of group II PAKs.

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Section: Chemistrymentioning

confidence: 99%

Section: ■ Chemistrymentioning

confidence: 99%

Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

et al. 2017

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“…Neuropeptide Y5 receptor antagonists may bring considerable progress in the treatment of obesity. Sakamoto et al 26 synthesized a series of spiroindoline derivatives and tested them as neuropeptide Y5 receptor antagonists. They studied the structure-activity-relationship of a spiroindoline class of compounds and identified them as effective in chronic obesity.…”

Section: Figure 6 Proposed Structure Of P-toluidine-2-merhyl-14-dinmentioning

confidence: 99%

1,4-Dinitro-1H-imidazoles

Suwiński¹

2015

Arkivoc

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“…Recently, a novel analog of MK‐0557, the spironolactone Y 5 R antagonist, was shown to maintain anti‐obesity effects in diet‐obese animals and is part of further investigations129. Based on the ongoing interest in obesity treatment and feeding responses, many further NPY antagonists were established within the last years, among them benzimidazole derivatives130, ureido derivatives131 or spirolindoline class compounds132 and many more133, all of them with good prospects to be future candidates in anti‐obesity therapies. Moreover, besides its impact on neurological diseases, the Y 2 R emerged as interesting target in obesity treatment as numerous studies reported on the Y 2 R‐selective agonist PYY(3–36) being capable to reduce hunger and food intake in humans134.…”

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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Novel orally active NPY Y5 receptor antagonists: Synthesis and structure–activity relationship of spiroindoline class compounds

Cited by 11 publications

References 36 publications

Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

1,4-Dinitro-1H-imidazoles

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

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