Oxindole Derivatives as Orally Active Potent Growth Hormone Secretagogues

Tokunaga, Teruhisa; Hume, W. Ewan; Umezome, Takashi; Okazaki, Kazuhiko; Ueki, Yoshitaka; Kumagai, Kazuo; Hourai, Shinji; Nagamine, Jun; Seki, Hitoshi; Taiji, Mutsuo; Noguchi, and Hiroshi; Nagata, Ryu

doi:10.1021/jm0103763

Cited by 268 publications

(79 citation statements)

References 36 publications

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“…However, subsequent series based on the spiropiperidine privileged structure, MK-677 being the most advanced prototype compound, exhibited favorable in vivo properties and have been investigated in several human clinical studies, including a phase II study for bone healing. A number of different series of nonpeptide GHS compounds, inspired by this pioneering work, were subsequently developed at different companies, including the highly conformationally constrained oxindole compounds from Tokunaga et al (2001Tokunaga et al ( , 2005 (Fig. 1).…”

mentioning

confidence: 99%

Overlapping Binding Site for the Endogenous Agonist, Small-Molecule Agonists, and Ago-allosteric Modulators on the Ghrelin Receptor

Holst

Frimurer²,

Mokrosiński³

et al. 2008

Mol Pharmacol

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A library of robust ghrelin receptor mutants with single substitutions at 22 positions in the main ligand-binding pocket was employed to map binding sites for six different agonists: two peptides (the 28-amino-acid octanoylated endogenous ligand ghrelin and the hexapeptide growth hormone secretagogue GHRP-6) plus four nonpeptide agonists-the original benzolactam L-692,429 [3-amino-3-methyl-N-(2,3,4,5-The strongest mutational effect with respect to decrease in potency for stimulation of inositol phosphate turnover was for all six agonists the GluIII:09-to-Gln substitution in the extracellular segment of TM-III. Likewise, all six agonists were affected by substitutions of PheVI:16, ArgVI:20, and PheVI:23 on the opposing face of transmembrane domain (TM) VI. Each of the agonists was also affected selectively by specific mutations. The mutational map of the ability of L-692,429 and GHRP-6 to act as allosteric modulators by increasing ghrelin's maximal efficacy overlapped with the common mutational map for agonism but it was not identical with the map for the agonist property of these small-molecule ligands. In molecular models, built over the inactive conformation of rhodopsin, low energy conformations of the nonpeptide agonists could be docked to satisfy many of their mutational hits. It is concluded that although each of the ligands in addition exploits other parts of the receptor, a large, common binding site for both small-molecule agonists-including ago-allosteric modulators-and the endogenous agonist is found on the opposing faces of TM-III and -VI of the ghrelin receptor.The gastrointestinal peptide hormone ghrelin is an important regulator of appetite, energy expenditure, and acute growth hormone secretion through interaction with the ghrelin receptors located mainly in the central nervous system (Tschöp et al., 2000). From a drug discovery point of view, these functions of ghrelin qualify ghrelin receptor agonists as anabolic compounds with potentials for treatment of, for example, cachexia.The initial agonists synthesized for the ghrelin receptor were peptides, sharing common structural features, including a central hydrophobic motif and a positive charge in the amidated C-terminal end. Despite relatively poor bioavailability and low therapeutic index/window, these peptides efficiently induced GH secretion in vitro as well as in vivo both in animal and human models (Bowers et al., 1984). GHRP-6 is a prototype for these peptides (Fig. 1). In an attempt to increase oral bioavailability, a series of nonpeptide compounds was subsequently developed. They were

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confidence: 99%

Overlapping Binding Site for the Endogenous Agonist, Small-Molecule Agonists, and Ago-allosteric Modulators on the Ghrelin Receptor

Holst

Frimurer²,

Mokrosiński³

et al. 2008

Mol Pharmacol

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“…It is also conceivable that the 2,5-dihydroxybenzoic acid that exhibited higher enantioselectivity might also provide an additional asset for chitosan, favoring the recognition of this reagent by the catalyst. Other additives were also tested using the template reaction, which produced product 3a in good yields along with lower enantioselectivity (Table 3, entries [3][4][5][6][7][8][9][10][11][12][13][14]. Moreover, considering that the reaction temperature is related to the enantioselectivity, the reaction was conducted at 0 °C.…”

Section: Resultsmentioning

confidence: 99%

“…Representative examples are: TMC-95A [9,10], Dioxibrassinine [11,12], SM-130686 [13], 3 -Hydroxygluoisatisin [14], and Convolutamydines ( Figure 1) [15]. Consequently, the 3-substituted-3-hydroxy-2-oxindole framework has been an intensively investigatedsynthetic target.…”

Section: Introductionmentioning

confidence: 99%

Chitosan Aerogel Catalyzed Asymmetric Aldol Reaction in Water: Highly Enantioselective Construction of 3-Substituted-3-hydroxy-2-oxindoles

Hui

Liu

et al. 2016

Catalysts

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“…For instance, various heterocyclic ring systems such as morpholine, pyrrolidine, piperidine, dimethylmorpholine, indoline etc. have been found as the fundamental scaffold components of several drugs in the market today [17,18]. The significance of these moieties are well understood by medicinal chemists since they play important role in molecular properties or whole molecule properties such as three dimensionality, scaffold rigidity, lipophilicity or polarity, and can determine molecular reactivity, metabolic stability, cellular activity, and toxicity.…”

Section: Anticancer Activitymentioning

confidence: 99%

Synthesis and Anti-Proliferative Activity of Biphenyl Derived 5-Substituted-Indolin-2-Ones

Meti¹,

Kamble²,

Kamble³

et al. 2017

Arch Chem Res

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A series of novel biphenyl derived 5-substituted-indolin-2-one derivatives were synthesized by the reaction of 6-chloro-5-(2-chloroethyl)-indolin-2-one 1 with cyclic secondary amines 2a-h followed by condensation of bromomethylcyanobiphenyl to afford the compounds 5a-h. The nitrile group of 5a-h was converted into tetrazole to obtain the compounds 7a-h and tetrazole of 7a-h was further ring transformed into oxadiazole to get compounds 8a-h. Molecular docking study of these previously unknown molecules was performed on PDB: 453D to analyze the interaction and preferred binding mode of synthesized molecules with DNA. Anti-proliferative activity of these newly synthesized compounds were evaluated against a panel of 60 human cancer cell lines at National Cancer Institute (NCI), Bethesda USA. Among these, seven (07) compounds were evaluated for their anticancer activity. Some of the compounds displayed potent anti-proliferative activity at 10 µM.

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Oxindole Derivatives as Orally Active Potent Growth Hormone Secretagogues

Cited by 268 publications

References 36 publications

Overlapping Binding Site for the Endogenous Agonist, Small-Molecule Agonists, and Ago-allosteric Modulators on the Ghrelin Receptor

Overlapping Binding Site for the Endogenous Agonist, Small-Molecule Agonists, and Ago-allosteric Modulators on the Ghrelin Receptor

Chitosan Aerogel Catalyzed Asymmetric Aldol Reaction in Water: Highly Enantioselective Construction of 3-Substituted-3-hydroxy-2-oxindoles

Synthesis and Anti-Proliferative Activity of Biphenyl Derived 5-Substituted-Indolin-2-Ones

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