当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies.

Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies.

Abstract：

:Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OX2R, which led to high OX1R selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OX1R antagonists.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Nagase H,Yamamoto N,Yata M,Ohrui S,Okada T,Saitoh T,Kutsumura N,Nagumo Y,Irukayama-Tomobe Y,Ishikawa Y,Ogawa Y,Hirayama S,Kuroda D,Watanabe Y,Gouda H,Yanagisawa M

doi

10.1021/acs.jmedchem.6b01418

subject

Has Abstract

pub_date

2017-02-09 00:00:00

pages

1018-1040

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

60

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Structure-activity studies of 5-[[4-(4,5-dihydro-2-oxazolyl) phenoxy]alkyl]-3-methylisoxazoles: inhibitors of picornavirus uncoating.

    abstract：:A series of substituted phenyl analogues of 5-[[4-(4,5-dihydro-2-oxazolyl) phenoxy]alkyl]-3-methylisoxazoles has been synthesized and evaluated in vitro against several human rhinovirus (HRV) serotypes. Substituents in the 2-position greatly enhanced activity when compared to the unsubstituted compound. Many of these ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00385a021

    authors： Diana GD,Oglesby RC,Akullian V,Carabateas PM,Cutcliffe D,Mallamo JP,Otto MJ,McKinlay MA,Maliski EG,Michalec SJ

    更新日期：1987-02-01 00:00:00

  • 8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists.

    abstract：:This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discove...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9000242

    authors： Gilligan PJ,He L,Clarke T,Tivitmahaisoon P,Lelas S,Li YW,Heman K,Fitzgerald L,Miller K,Zhang G,Marshall A,Krause C,McElroy J,Ward K,Shen H,Wong H,Grossman S,Nemeth G,Zaczek R,Arneric SP,Hartig P,Robertson DW,T

    更新日期：2009-05-14 00:00:00

  • Antagonists of slow-reacting substance of anaphylaxis. 1. Pyrido[2,1-b]quinazolinecarboxylic acid derivatives.

    abstract：:Members of a series of basic amide and ester derivatives of 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids were prepared and evaluated for their ability to prevent slow-reacting substance of anaphylaxis (SRS-A) induced contractions of guinea pig ilea. The results indicate that the presence of a branched-cha...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00365a016

    authors： Tilley JW,Levitan P,Welton AF,Crowley HJ

    更新日期：1983-11-01 00:00:00

  • Antiandrogenic steroidal sulfonylpyrazoles.

    abstract：:The steroidal sulfonylpyrazole 1 bound to the rat ventral prostate androgen receptor in vitro; it inhibited testosterone propionate induced increases in ventral prostate weight in vivo in the castrated, immature male rat with an ED50 of 15 mg/kg po. Compound 1 lacked androgenic activity in vivo in contrast to the pare...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00170a008

    authors： Christiansen RG,Bell MR,D'Ambra TE,Mallamo JP,Herrmann JL,Ackerman JH,Opalka CJ,Kullnig RK,Winneker RC,Snyder BW

    更新日期：1990-08-01 00:00:00

  • Soluble 3',6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period.

    abstract：:Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800648y

    authors： Vougogiannopoulou K,Ferandin Y,Bettayeb K,Myrianthopoulos V,Lozach O,Fan Y,Johnson CH,Magiatis P,Skaltsounis AL,Mikros E,Meijer L

    更新日期：2008-10-23 00:00:00

  • Quantitative analysis of histone demethylase probes using fluorescence polarization.

    abstract：:We previously reported methylstat as a selective inhibitor of jumonji C domain-containing histone demethylases (JHDMs). Herein, we describe the synthesis of a fluorescent analogue of methylstat and its application as a tracer in fluorescence polarization assays. Using this format, we have evaluated the binding affinit...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm3018628

    authors： Xu W,Podoll JD,Dong X,Tumber A,Oppermann U,Wang X

    更新日期：2013-06-27 00:00:00

  • Design and synthesis of high affinity inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferases directed by ligand efficiency dependent lipophilicity (LELP).

    abstract：:N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both P...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm500066b

    authors： Rackham MD,Brannigan JA,Rangachari K,Meister S,Wilkinson AJ,Holder AA,Leatherbarrow RJ,Tate EW

    更新日期：2014-03-27 00:00:00

  • Fragment-based drug design: how big is too big?

    abstract：:Much has been discussed about the proper physicochemical properties (e.g., molecular weight, hydrophobicity, etc.) that should be considered when utilizing fragment leads in drug design. However, little has been reported as to what emphasis, if any, should be placed on the potency of the resulting fragment leads. In t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060511h

    authors： Hajduk PJ

    更新日期：2006-11-30 00:00:00

  • Further development of hydrogen bond functions for use in determining energetically favorable binding sites on molecules of known structure. 1. Ligand probe groups with the ability to form two hydrogen bonds.

    abstract：:The directional properties of hydrogen bonds play a major role in determining the specificity of intermolecular interactions. An energy function which takes explicit account of these properties has been developed for use in the determination of energetically favorable ligand binding sites on molecules of known structu...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00053a018

    authors： Wade RC,Clark KJ,Goodford PJ

    更新日期：1993-01-08 00:00:00

  • Synthesis and biological activity of 5'-substituted 5-fluoropyrimidine nucleosides.

    abstract：:5'-Deoxy-5-fluorouridine (5'-dFUrd, 1) possesses a significantly higher chemotherapeutic index than other fluoropyrimidines as a result of its being selectivity cleaved in tumors to 5-fluorouracil (FUra) by uridine phosphorylase. Because 1 is a relatively poor substrate for this enzyme, we synthesized a series of 5'-d...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00350a024

    authors： Ajmera S,Danenberg PV

    更新日期：1982-08-01 00:00:00

  • Synthesis and physicochemical properties of sulfamate derivatives as topical antiglaucoma agents.

    abstract：:Several imidazolylphenyl sulfamate and (imidazolylphenoxy)alkyl sulfamate derivatives were synthesized and evaluated as topically active carbonic anhydrase inhibitors. Water solubility, pKa, carbonic anhydrase inhibition, and partition coefficient for the compounds were measured. Sulfamic acid 2-[4-(1H-imidazol-1-yl)p...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00104a003

    authors： Lo YS,Nolan JC,Maren TH,Welstead WJ Jr,Gripshover DF,Shamblee DA

    更新日期：1992-12-25 00:00:00

  • Novel triazole ribonucleoside down-regulates heat shock protein 27 and induces potent anticancer activity on drug-resistant pancreatic cancer.

    abstract：:A series of novel 3-arylethynyltriazolyl ribonucleosides were synthesized and assessed for their anticancer activity on the drug-resistant pancreatic cancer cell line MiaPaCa-2. Among them, one compound exhibited potent apoptosis-inducing properties and anticancer activity against the pancreatic cancer model MiaPaCa-2...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm900960v

    authors： Xia Y,Liu Y,Wan J,Wang M,Rocchi P,Qu F,Iovanna JL,Peng L

    更新日期：2009-10-08 00:00:00

  • Gonadotropin-releasing hormone antagonists with N omega-triazolylornithine, -lysine, or -p-aminophenylalanine residues at positions 5 and 6.

    abstract：:In order to be used as fertility regulators in humans, gonadotropin releasing hormone (GnRH) antagonists must be extremely potent and long acting and exhibit negligible side effects such as stimulating histamine release. To this aim, we have recently synthesized a series of analogues with the standard Ac-DNal1-DCpa2-D...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00101a003

    authors： Rivier J,Porter J,Hoeger C,Theobald P,Craig AG,Dykert J,Corrigan A,Perrin M,Hook WA,Siraganian RP

    更新日期：1992-11-13 00:00:00

  • 6-Azido-7-nitro-1,4-dihydroquinoxaline-2,3-dione (ANQX) forms an irreversible bond to the active site of the GluR2 AMPA receptor.

    abstract：:AMPA receptors mediate fast excitatory synaptic transmission and are essential for synaptic plasticity. ANQX, a photoreactive AMPA receptor antagonist, is an important biological probe used to irreversibly inactivate AMPA receptors. Here, using X-ray crystallography and mass spectroscopy, we report that ANQX forms two...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm701517b

    authors： Cruz LA,Estébanez-Perpiñá E,Pfaff S,Borngraeber S,Bao N,Blethrow J,Fletterick RJ,England PM

    更新日期：2008-09-25 00:00:00

  • Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides.

    abstract：:The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00442

    authors： Russell S,Rahmani R,Jones AJ,Newson HL,Neilde K,Cotillo I,Rahmani Khajouei M,Ferrins L,Qureishi S,Nguyen N,Martinez-Martinez MS,Weaver DF,Kaiser M,Riley J,Thomas J,De Rycker M,Read KD,Flematti GR,Ryan E,Tanghe S,R

    更新日期：2016-11-10 00:00:00

  • Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors.

    abstract：:Activators of nuclear factor-erythroid 2-related factor 2 (NRF2) could lead to promising therapeutics for prevention and treatment of oxidative stress and inflammatory disorders. Ubiquitination and subsequent degradation of the transcription factor NRF2 is mediated by Kelch-like ECH-associated protein-1 (KEAP1). Inhib...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b01133

    authors： Richardson BG,Jain AD,Potteti HR,Lazzara PR,David BP,Tamatam CR,Choma E,Skowron K,Dye K,Siddiqui Z,Wang YT,Krunic A,Reddy SP,Moore TW

    更新日期：2018-09-13 00:00:00

  • Oxadiazoles in medicinal chemistry.

    abstract：:Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm2013248

    authors： Boström J,Hogner A,Llinàs A,Wellner E,Plowright AT

    更新日期：2012-03-08 00:00:00

  • Enzymatic release of antitumor ether lipids by specific phospholipase A2 activation of liposome-forming prodrugs.

    abstract：:An enzymatically activated liposome-based drug-delivery concept involving masked antitumor ether lipids (AELs) has been investigated. This concept takes advantage of the cytotoxic properties of AEL drugs as well as the membrane permeability enhancing properties of these molecules, which can lead to enhanced drug diffu...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm031029r

    authors： Andresen TL,Davidsen J,Begtrup M,Mouritsen OG,Jørgensen K

    更新日期：2004-03-25 00:00:00

  • Development of a novel class of glucose transporter inhibitors.

    abstract：:On the basis of our finding that the antitumor effect of 5-{4-[(1-methylcyclohexyl)methoxy]benzyl}thiazolidine-2,4-dione, a thiazolidinedione peroxisome proliferator-activated receptor (PPAR)γ agonist, was, in part, attributable to its ability to block glucose uptake independently of PPARγ, we used its PPARγ-inactive ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,收录出版

    doi：10.1021/jm300015m

    authors： Wang D,Chu PC,Yang CN,Yan R,Chuang YC,Kulp SK,Chen CS

    更新日期：2012-04-26 00:00:00

  • Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography.

    abstract：:2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPC...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9902234

    authors： Xing D,Chen P,Keil R,Kilts CD,Shi B,Camp VM,Malveaux G,Ely T,Owens MJ,Votaw J,Davis M,Hoffman JM,BaKay RA,Subramanian T,Watts RL,Goodman MM

    更新日期：2000-02-24 00:00:00

  • Discovery and Optimization of a Porcupine Inhibitor.

    abstract：:Wnt proteins regulate various cellular functions and serve distinct roles in normal development throughout life. Wnt signaling is dysregulated in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoleates the Wnts and hence is essential for their secretion and functi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b00507

    authors： Duraiswamy AJ,Lee MA,Madan B,Ang SH,Tan ES,Cheong WW,Ke Z,Pendharkar V,Ding LJ,Chew YS,Manoharan V,Sangthongpitag K,Alam J,Poulsen A,Ho SY,Virshup DM,Keller TH

    更新日期：2015-08-13 00:00:00

  • Thiazolothiazepine inhibitors of HIV-1 integrase.

    abstract：:A series of thiazolothiazepines were prepared and tested against purified human immunodeficiency virus type-1 integrase (HIV-1 IN) and viral replication. Structure-activity studies reveal that the compounds possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups are in general more potent against purifie...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm990047z

    authors： Neamati N,Turpin JA,Winslow HE,Christensen JL,Williamson K,Orr A,Rice WG,Pommier Y,Garofalo A,Brizzi A,Campiani G,Fiorini I,Nacci V

    更新日期：1999-08-26 00:00:00

  • Targeting the MKK7-JNK (Mitogen-Activated Protein Kinase Kinase 7-c-Jun N-Terminal Kinase) Pathway with Covalent Inhibitors.

    abstract：:The protein kinase MKK7 is linked to neuronal development and the onset of cancer. The field, however, lacks high-quality functional probes that would allow for the dissection of its detailed functions. Against this background, we describe an effective covalent inhibitor of MKK7 based on the pyrazolopyrimidine scaffol...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b00102

    authors： Wolle P,Hardick J,Cronin SJF,Engel J,Baumann M,Lategahn J,Penninger JM,Rauh D

    更新日期：2019-03-14 00:00:00

  • Exploiting the therapeutic potential of 8-β-d-glucopyranosylgenistein: synthesis, antidiabetic activity, and molecular interaction with islet amyloid polypeptide and amyloid β-peptide (1-42).

    abstract：:8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm501069h

    authors： Jesus AR,Dias C,Matos AM,de Almeida RF,Viana AS,Marcelo F,Ribeiro RT,Macedo MP,Airoldi C,Nicotra F,Martins A,Cabrita EJ,Jiménez-Barbero J,Rauter AP

    更新日期：2014-11-26 00:00:00

  • Studies on some derivatives of oxamniquine.

    abstract：:On the basis of the remarkable biological similarities between hycanthone and oxamniquine and as a sequel to our finding that some esters of hycanthone are active against hycanthone-resistant schistosomes, we prepared oxamniquine acetate, oxamniquine N-methylcarbamate, and four substituted phenylsulfonohydrazones of o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00403a024

    authors： el-Hamouly W,Pica-Mattoccia L,Cioli D,Schwartz HM,Archer S

    更新日期：1988-08-01 00:00:00

  • Bicyclic Helical Peptides as Dual Inhibitors Selective for Bcl2A1 and Mcl-1 Proteins.

    abstract：:A 26-residue peptide BimBH3 binds indiscriminately to multiple oncogenic Bcl2 proteins that regulate apoptosis of cancer cells. Specific inhibition of the BimBH3-Bcl2A1 protein-protein interaction was obtained in vitro and in cancer cells by shortening the peptide to 14 residues, inserting two cyclization constraints ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00010

    authors： D de Araujo A,Lim J,Wu KC,Xiang Y,Good AC,Skerlj R,Fairlie DP

    更新日期：2018-04-12 00:00:00

  • Synthesis and evaluation of keto-glutamine analogues as potent inhibitors of severe acute respiratory syndrome 3CLpro.

    abstract：:The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0494873

    authors： Jain RP,Pettersson HI,Zhang J,Aull KD,Fortin PD,Huitema C,Eltis LD,Parrish JC,James MN,Wishart DS,Vederas JC

    更新日期：2004-12-02 00:00:00

  • Exploring the scaffold universe of kinase inhibitors.

    abstract：:The scaffold concept was applied to systematically determine, analyze, and compare core structures of kinase inhibitors. From publicly available inhibitors of the human kinome, scaffolds and cyclic skeletons were systematically extracted and organized taking activity data, structural relationships, and retrosynthetic ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm501237k

    authors： Hu Y,Bajorath J

    更新日期：2015-01-08 00:00:00

  • Flavones. 2. Synthesis and structure-activity relationship of flavodilol and its analogues, a novel class of antihypertensive agents with catecholamine depleting properties.

    abstract：:(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple f...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00121a034

    authors： Wu ES,Cole TE,Davidson TA,Dailey MA,Doring KG,Fedorchuk M,Loch JT 3rd,Thomas TL,Blosser JC,Borrelli AR

    更新日期：1989-01-01 00:00:00

  • Synthetic mimics of antimicrobial peptides from triaryl scaffolds.

    abstract：:In this report, we describe the synthesis of a new series of small amphiphilic aromatic compounds that mimic the essential properties of cationic antimicrobial peptides using Suzuki-Miyaura coupling. The new design allowed the easy tuning of the conformational restriction, controlled by introduction of intramolecular ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm101410t

    authors： Thaker HD,Sgolastra F,Clements D,Scott RW,Tew GN

    更新日期：2011-04-14 00:00:00