Structure–activity relationships of the oxindole growth hormone secretagogues

Tokunaga, Teruhisa; Hume, W. Ewan; Nagamine, Jun; Kawamura, Tetsuya; Taiji, Mutsuo; Nagata, Ryu

doi:10.1016/j.bmcl.2005.02.042

Cited by 136 publications

(48 citation statements)

References 14 publications

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“…These substances were quinazolinone derivates [67], ligands based on tri-substituted 1,2,4-triazole structure [68,69], tetralin carboxamide [70,71] isoxazole carboxamide [72], 2,4-diaminopyrimidines [73], oxindole [74], piperazine-bisamide [75] GHSR ligands as well as R-prolinol-derivate agonists [76]. …”

Section: Gpcrs As Targets For Treatment Of Cachexia and Obesitymentioning

confidence: 99%

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

et al. 2012

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The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.

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Section: Gpcrs As Targets For Treatment Of Cachexia and Obesitymentioning

confidence: 99%

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

et al. 2012

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“…For example, the convolutamydines, 2 and the 3-hydroxywelwitindolinones are part of a growing list of biologically active 3-hydroxyoxindoles ( Figure 1). 3 3-Hydroxyoxindoles with a quaternary benzylic centre are a useful class of compounds also found in several drug candidates, including the potent, orally active growth hormone secretagogue SM-130686, 4 a drug that currently is under investigation for the treatment of growth hormone deficiency and other medical conditions (Figure 1). 5 There are a number of reports on the enantioselective formation of quaternary carbon centers at the 3-position of oxindoles.…”

Section: Graphical Abstractmentioning

confidence: 99%

A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles

Buckley

D.‐R.

2013

Tetrahedron Letters

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A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles his item ws sumitted to voughorough niversity9s snstitutionl epository y theGn uthorF Citation: fguviD fFF nd pix ¡ exhi hFEFD fFD PHIQF e tlytiD mild nd effiient protool for the gEQ eril hydroxyltion of oxindolesF etrE hedron vettersD SR @VAD ppFVRQEVRTF Additional Information:• xysgiX this is the uthor9s version of work tht ws epted for pulition in etrhedron vettersF ghnges resulting from the pulishE ing proessD suh s peer reviewD editingD orretionsD struturl formtE tingD nd other qulity ontrol mehnisms my not e refleted in this doumentF ghnges my hve een mde to this work sine it ws suE mitted for pulitionF e definitive version ws susequently pulished tX httpXGGdxFdoiForgGIHFIHITGjFtetletFPHIPFIIFHVQ Methods for functionalization of the oxindole nucleus are of significant value in medicinal chemistry and natural product synthesis.1 Due to their unprecedented structural diversity, biological activity and structural challenge, oxindoles continue to attract the interest of chemists and biologists alike. For example, the convolutamydines, 2 and the 3-hydroxywelwitindolinones are part of a growing list of biologically active 3-hydroxyoxindoles (Figure 1).3 3-Hydroxyoxindoles with a quaternary benzylic centre are a useful class of compounds also found in several drug candidates, including the potent, orally active growth hormone There are a number of reports on the enantioselective formation of quaternary carbon centers at the 3-position of oxindoles.6 For example, Hartwig first reported the palladiumcatalysed synthesis of oxindoles by amide α-arylation with ees of up to 67%; 7 This was later improved upon by Kündig using modified N-heterocyclic carbenes 8 and Marsden has reported several methods for the synthesis of 3-hydroxy-and 3-aminooxindoles. 9Copper-mediated processes have also recently been employed to prepare quaternary C-3 oxindoles by both the Kündig 10 and Taylor groups.11 Also of note are the recent reports by Franz,12 who has reported the asymmetric direct addition of nucleophiles to isatins using chiral Lewis acids, and Shibata and Toru who have reported the asymmetric C-3 hydroxylation of oxindoles also using chiral Lewis acids, with an oxaziridine as the stoicheiometric oxidant. 13 Thus owing to the significance of the oxindole structural motif, the development of catalytic methods for the synthesis of oxindoles bearing a C-3 hydroxy quaternary centre is highly desirable.Gassman and Halweg reported the air oxidation of oxindoles to isatins (Scheme 1) through treatment of 3-methylthiooxindoles with a strong stoicheiometric base and air; strict anhydrous conditions were required in order to prevent degradation of the isatin to the corresponding anthranilic acid.14 We also noted the recent report from Curran and co-workers, 15 where the attempted removal of the trimethylsilyl (TMS) group from 1 resulted in 3-hydroxy-1,3-dihydroindol-2-one 2 being the sole product of the reaction (Scheme 2). Careful investigation of...

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“…Some of those have been radio-labeled for in vivo imaging. Clinical trials have been performed for ligands at CRF1 receptors [39,[42][43][44][45][46][47], at orexin receptors [48,49], at the NPY receptors [50,51], the opioid receptors [52], melanocortin -4-receptors (MC4-R) [53][54][55], melanin concentrating hormone receptors (MCH1-R) [56] and growth hormone secretagogue receptor 1 (ghrelin; GHS1-R) [57,58].…”

Section: Hypothalamus As a Potential Target For Drug Development In Tmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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Structure–activity relationships of the oxindole growth hormone secretagogues

Cited by 136 publications

References 14 publications

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

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