2-Acyl-3-carboxyl-tetrahydroisoquinoline Derivatives: Mixed-Type PTP1B Inhibitors without PPARγ Activation.


:A novel series of 2-acyl-3-carboxyl-tetrahydroisoquinoline derivatives were synthesized and biologically evaluated. Among them, (S)-2-{(E)-3-furan-2-ylacryloyl}-7-[(2E,4E)-5-(2,4,6-trifluorophenyl)penta-2,4-dienyloxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (compound 17u) was identified as a potent protein tyrosine phosphatase 1B (PTP1B) inhibitor without peroxisome proliferator-activated receptor (PPAR) γ activation: PTP1B inhibition IC50=0.19 µM and PPARγ ΕC50>10 µM. Compound 17u exhibited mixed-type inhibition for PTP1B, and this mode of inhibition was rationalized by computational ligand docking into the catalytic and allosteric sites of PTP1B. Compound 17u also showed high oral absorption at 10 mg/kg (per os (p.o.), Cmax=4.67 µM) in rats, significantly reduced non-fasting plasma glucose and triglyceride levels with no side effects at 30 mg/kg/d (p.o.) for 4 weeks, and attenuated elevations in plasma glucose levels in the oral glucose tolerance test performed 24 h after its final administration in db/db mice. In conclusion, the substituted 2-acyl-3-carboxyl-tetrahydroisoquinoline is a novel scaffold of mixed-type PTP1B inhibitors without PPARγ activation, and compound 17u has potential as an efficacious and safe anti-diabetic drug as well as a useful tool for investigations on the physiological and pathophysiological effects of mixed-type PTP1B inhibition.


Morishita K,Shoji Y,Fukui M,Ito Y,Kitao T,Ozawa SI,Hirono S,Shirahase H




Has Abstract


2018-01-01 00:00:00












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    abstract::Five compounds have been isolated from the dried whole plants of Selaginella uncinata, two of them were new chromone glycosides, 5-hydroxy-2,6,8-trimethylchromone 7-O-beta-D-glucopyranoside (uncinoside A) and 5-acetoxyl-2,6,8-trimethylchromone 7-O-beta-D-glucopyranoside (uncinoside B). Their structures were elucidated...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Ma LY,Ma SC,Wei F,Lin RC,But PP,Lee SH,Lee SF

    更新日期:2003-11-01 00:00:00

  • Synthesis of peptides mimicking chemokine receptor CCR5 and their inhibitory effects against HIV-1 infection.

    abstract::Peptides mimicking chemokine receptor CCR5 were synthesized and their anti-HIV-1 activities evaluated. Prepared compounds, especially a sulfated derivatives, showed significant anti-HIV-1 activities. Furthermore, a hybrid molecule linked to an N-carbomethoxycarbonyl-prolyl-phenylalanine (CPF) moiety had a greater effe...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Konishi K,Ikeda K,Achiwa K,Hoshino H,Tanaka K

    更新日期:2000-02-01 00:00:00

  • Amino acids and peptides. XX. Preparation of beta-cyclododecyl aspartate and its application to synthesis of fibronectin- and laminin-related peptides.

    abstract::beta-Cyclododecyl aspartate was prepared and its application to peptide synthesis was examined. Derivatives of beta-cyclododecyl aspartate are more likely to crystallize and should be useful for peptide synthesis. The cyclododecyl ester was much stable to bases than the benzyl ester and rather more stable than the cyc...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Kawasaki K,Murakami T,Koshino K,Namikawa M,Maeda M,Hama T,Mayumi T

    更新日期:1994-04-01 00:00:00

  • Convenient one-pot synthesis of 2-oxazolines from carboxylic acids.

    abstract::Simple one-pot methods for preparation of 2-oxazolines have been developed using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). Treatment of a mixture of carboxylic acids and 2-haloethylammonium salts with DMT-MM in methanol followed by refluxing in the presence of KOH gives oxazolines. ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Hioki K,Takechi Y,Kimura N,Tanaka H,Kunishima M

    更新日期:2008-12-01 00:00:00

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    abstract::Six new dammarane-type triterpene diglycosides with a hydroperoxide group, floralginsenosides A, B, C, D, E, and F, were isolated from ginseng flower, the flower buds of Panax ginseng C. A. MEYER, together with seven known dammarane-type triterpene oligoglycosides. The structures of new floralginsenosides were elucida...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Yoshikawa M,Sugimoto S,Nakamura S,Matsuda H

    更新日期:2007-04-01 00:00:00

  • gamma-Pyrones from Gonystylus keithii, as new inhibitors of parathyroid hormone (PTH)-induced Ca release from neonatal mouse calvaria.

    abstract::New gamma-pyrones, 9'-oxopodopyrone (3) and 8-methyl-9'-oxopodopyrone (4) were isolated from the leaves of Gonystylus keithii, along with known gamma-pyrones, 10'-oxopodopyrone (1) and 8-methyl-10'-oxopodopyrone (2). These gamma-pyrones markedly inhibited the bovine parathyroid hormone (PTH)-induced Ca release from ne...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Kanazawa T,Ohkawa Y,Kuda T,Minobe Y,Tani T,Nishizawa M

    更新日期:1997-06-01 00:00:00

  • Kobophenol A inhibits sodium nitroprusside-induced cardiac H9c2 cell death through suppressing activation of JNK and preserving mitochondrial anti-apoptotic Bcl-2 and Mcl-1.

    abstract::Sodium nitroprusside (SNP) releases nitric oxide (NO), a powerful vasodilator, and thus widely used in intensive care unit for treating hypertension emergency. However, cardiac toxicity after SNP administration is a clinical problem. For finding a natural compound that suppressing SNP-induced cardiac toxicity, we test...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Lee SR,Kwak JH,Noh SJ,Pronto JR,Ko KS,Rhee BD,Xu Z,Kim N,Han J

    更新日期:2014-01-01 00:00:00

  • Chiral Calcium-Catalyzed Asymmetric Epoxidation Reactions Using Hydrogen Peroxide as the Terminal Oxidant.

    abstract::Asymmetric epoxidation reactions of chalcone derivatives catalyzed by chiral calcium complexes using hydrogen peroxide were developed. The epoxidation reactions proceeded smoothly to afford the desired products in good yields with good enantioselectivities. This is the first example of chiral calcium-catalyzed asymmet...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Yamashita Y,Macor JA,Fushimi S,Tsubogo T,Kobayashi S

    更新日期:2018-01-01 00:00:00

  • Preparation on oligostilbenes of isorhapontigenin by oxidative coupling reaction.

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    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Yao CS,Zhou LX,Lin M

    更新日期:2004-02-01 00:00:00

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    abstract::Microdialysis sampling method coupled to high-performance liquid chromatography with UV detection was applied to continuous monitoring of in vivo unbound flomoxef concentration in rat blood. By comparison with ultrafiltration method, it was demonstrated that it gave reliable results for the unbound drug monitoring in ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Saisho Y,Umeda T

    更新日期:1991-03-01 00:00:00

  • Inhibitory effects of 3-O-acyl-(+)-catechins on Epstein-Barr virus activation.

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    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Uesato S,Taniuchi K,Kumagai A,Nagaoka Y,Seto R,Hara Y,Tokuda H,Nishino H

    更新日期:2003-12-01 00:00:00

  • Triterpenoid saponins from Ardisia crenata and their inhibitory activity on cAMP phosphodiesterase.

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    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Jia Z,Koike K,Nikaido T,Ohmoto T,Ni M

    更新日期:1994-11-01 00:00:00

  • Characteristics of hyaluronate-hydroxyethyl acrylate blend gel and release of cationic amphiphilic solutes.

    abstract::Hyaluronate-hydroxyethyl acrylate blend gel (HA-PHEA) were prepared to modify the brittleness of hyaluronate gel (HA) and the characteristics of HA-PHEA gel were compared with those of HA and polyhydroxyethyl acrylate (PHEA) gels. These gels were high in water content and transparent. HA-PHEA gel was improved in visco...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Jin Y,Yamanaka J,Sato S,Miyata I,Yomota C,Yonese M

    更新日期:2002-10-01 00:00:00

  • Antiulcer activities of glycyrrhetinic acid derivatives in experimental gastric lesion models.

    abstract::Glycyrrhetinic acid (Ia) and eighteen related derivatives were examined for antiulcer activity using stress-induced gastric lesions (restraint plus water immersion at 25 degrees C) in mice and rats as screening tests. Among the compounds tested, dihemiphthalate derivatives of 18 alpha- or 18 beta-olean-12-ene-3 beta,3...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Yano S,Harada M,Watanabe K,Nakamaru K,Hatakeyama Y,Shibata S,Takahashi K,Mori T,Hirabayashi K,Takeda M

    更新日期:1989-09-01 00:00:00

  • Lobophytones H-N, Biscembranoids from the Chinese soft coral Lobophytum pauciflorum.

    abstract::Chemical examination of a Chinese soft coral Lobophytum pauciflorum resulted in the isolation of seven new biscembranoids, named lobophytones H-N (1-7). Their structures were determined by interpretation of 1D- and 2D-NMR (correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), heteronuclear mu...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Yan P,Deng Z,van Ofwegen L,Proksch P,Lin W

    更新日期:2010-12-01 00:00:00

  • A cytotoxic and apoptosis-inducing sesquiterpenoid isolated from the aerial parts of Artemisia princeps PAMPANINI (Sajabalssuk).

    abstract::Repeated silica gel and octadecyl silica gel (ODS) column chromatography of the aerial parts of Artemisia princeps PAMPANINI (Sajabalssuk) led to the isolation of a new sesquiterpenoid, 3-((S)-2-methylbutyryloxy)-costu-1(10),4(5)-dien-12,6 alpha-olide (2), along with two previously reported sesquiterpenoids: 8 alpha-a...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Bang MH,Han MW,Song MC,Cho JG,Chung HG,Jeong TS,Lee KT,Choi MS,Kim SY,Baek NI

    更新日期:2008-08-01 00:00:00

  • Six new presenegenin glycosides, reiniosides A--F, from Polygala reinii root.

    abstract::Six new oleanane-type triterpene saponins, called reiniosides A-F, were isolated from the roots of Polygala reinii Fr. et Sav. and their structures were elucidated by spectroscopic and chemical means. ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Miyase T,Saitoh H,Shiokawa K,Ueno A

    更新日期:1995-03-01 00:00:00

  • Preparation and properties of a mitomycin C-albumin conjugate.

    abstract::Mitomycin C, an anti-neoplastic agent, was covalently attached to bovine serum albumin through various kinds of spacers such as glutaryl, succinyl, trans-aconityl, methylsuccinyl and the trimellityl group. The prior acylation of albumin not only prevented protein polymerization in the presence of carbodiimide, but als...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Kaneo Y,Tanaka T,Iguchi S

    更新日期:1990-09-01 00:00:00

  • Agents for the treatment of overactive detrusor. VI. Synthesis and pharmacological properties of acetamide derivatives bearing cyclic amines in N-substituents.

    abstract::With the aim of improving of the efficacy and decreasing the side effects of oxybutynin (1), N-[(tetrahydro-3- or 4-pyridyl)methyl]-, N-(4-piperidyl)-, and N-(3- or 4-piperidylalkyl)-2-hydroxyacetamides (3a-n, 4a-g) and the related carboxamides (3o-r, 4h-k, 13', 17) were synthesized and evaluated for inhibitory activi...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Taniguchi K,Tsubaki K,Mizuno H,Take K,Okumura K,Terai T,Shiokawa Y

    更新日期:1994-01-01 00:00:00

  • Synthesis, structure and cytostatic activity of a series of N-substituted 3,4-diphenyl-1H-pyrrole-2,5-diones.

    abstract::A series of N-substituted 3,4-diphenyl-1H-pyrrole-2,5-diones (diphenylmaleimides) (IV) were synthesized and tested for cytostatic activity. Compounds IVa--k were prepared from diphenylmaleic anhydride or its dinitro derivative (V or VI) and the corresponding amine. Compounds IVl--n were obtained by reaction of 3-(p-ni...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Fernández Braña M,Fernández A,Garrido M,López Rodríguez ML,Morcillo MJ,Sanz AM

    更新日期:1989-10-01 00:00:00

  • Synthesis of BMS-309403-related compounds, including [¹⁴C]BMS-309403, a radioligand for adipocyte fatty acid binding protein.

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    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Okada T,Hiromura M,Otsuka M,Enomoto S,Miyachi H

    更新日期:2012-01-01 00:00:00

  • Immunohistochemical demonstration of calcium-binding protein regucalcin in the tissues of rats: the protein localizes in liver and brain.

    abstract::A calcium-binding protein, regucalcin, was isolated from rat liver cytosol. Rabbit-anti-regucalcin antiserum, which was raised against regucalcin conjugated by glutaraldehyde to bovine serum albumin, was applied to glutaraldehyde-fixed whole mounts and subsequently visualized using the peroxidase-antiperoxidase method...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Yamaguchi M,Isogai M,Kato S,Mori S

    更新日期:1991-06-01 00:00:00

  • Synthesis and Diels-Alder reactivity of ortho-carbazolequinones.

    abstract::Oxidation of 2- and 3-hydroxycarbazoles with Frémy's salt gave the corresponding ortho-carbazolequinones. These molecules react as carbodienophiles in Diels-Alder reaction with 1-acetoxy-1,3-butadiene and 1,3-cyclopentadiene to provide the novel benzocarbazolequinone structures 15, 16, 18 and 19. ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Compain-Batissou M,Latreche D,Gentili J,Walchshofer N,Bouaziz Z

    更新日期:2004-09-01 00:00:00

  • New acetylenic glucosides from Carthamus tinctorius.

    abstract::Two new acetylenic glucosides, 4',6'-acetonide-8Z-decaene-4,6-diyne-1-O-beta-D-glucopyranoside named carthamoside A(1) (1) and 4,6-decadiyne-1-O-beta-D-glucopyranoside named carthamoside A(2) (2), along with one known acetylenic glucoside, 8Z-decaene-4,6-diyne-1-O-beta-D-glucopyranoside (3), have been isolated from th...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Zhou YZ,Ma HY,Chen H,Qiao L,Yao Y,Cao JQ,Pei YH

    更新日期:2006-10-01 00:00:00

  • Detection and identification of loline and its analogues in horse urine.

    abstract::Several kinds of loline-type alkaloids, norloline, loline, N-acetylnorloline, N-acetylloline, N-formylnorloline, N-formylloline and N-methylloline were detected in the urine of race-horses. Furthermore, a new compound of the alkaloids, N-senecioylnorloline, was also found and identified. These compounds were mainly id...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Takeda A,Suzuki E,Kamei K,Nakata H

    更新日期:1991-04-01 00:00:00

  • Synthesis and antibacterial activities of optically active substituted 1,2-dihydro-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids.

    abstract::A series of optically active substituted 1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids was prepared via optically active 2-methyl-4,5-difluoroindoline (10) and tested for antibacterial activities. Among them, (2S)-9-[(3R,1'S)-3-(1'-amino)ethyl-1-pyrrolidinyl]-8-fluoro-1,2-dihydro- 2- methyl-6-oxo-6H-...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Tsuji K,Tsubouchi H,Ishikawa H

    更新日期:1995-10-01 00:00:00

  • Benzoxazines. II. Synthesis, conformational analysis, and structure--activity relationships of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives as potent and long-acting serotonin-3 (5-HT3) receptor antagonists.

    abstract::A series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5HT3) receptor antagonistic activities by means of assays of 5-HT3 receptor binding and the ability to antagonize the von Bezold-Jarisch reflex in rats. Replacement of the 1,4-benzoxazine ring with a 1,4...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Kuroita T,Marubayashi N,Sano M,Kanzaki K,Inaba K,Kawakita T

    更新日期:1996-11-01 00:00:00

  • Hapten synthesis for (+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tet rahydro-8H-pyrido[4',3':4,5]thieno[3,2-f] triazolo[4,3-a][1,4]diazepine (E6123).

    abstract::(+)-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4, 5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f]triazolo[4,3-a] [1,4]diazepine (E6123) is a very potent platelet-activating factor (PAF) receptor antagonist and shows potent anti-PAF activities at the microgram level in a variety of animal models. In ord...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Miyazawa S,Okano K,Kawahara T,Machida Y,Yamatsu I

    更新日期:1992-03-01 00:00:00

  • Two cangorosin A type triterpene dimers from Maytenus chuchuhuasca.

    abstract::Two new cangorosin A type triterpene dimers, which composed of two triterpene units jointed by two ether linkages between the A and B rings, were isolated from the Brazilian medicinal plant "xuxuá" (Maytenus chuchuhuasca). Structures of new isolates, xuxuasins A (1) and B (2), were established based on several spectro...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Shirota O,Sekita S,Satake M,Morita H,Takeya K,Itokawa H

    更新日期:2004-09-01 00:00:00

  • Three new limonoids from Cipadessa cinerascens.

    abstract::Three new limonoids, cipadesins D--F (1--3), together with 8,15-dihydroxy-13E-labdane, beta-sitosterol and beta-daucosterol, were isolated from the leaves and bark of Cipadessa cinerascens. Their structures were elucidated by spectral evidence. X-Ray crystallographic analysis confirmed the structure of 1. ...

    journal_title:Chemical & pharmaceutical bulletin

    pub_type: 杂志文章


    authors: Yuan XH,Li BG,Xu CX,Zhou M,Qi HY,Zhang GL

    更新日期:2007-06-01 00:00:00