当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2.

Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2.

Abstract：

:It is necessary for aldosterone synthase (CYP11B2) inhibitors to have both high potency and high selectivity over 11β-hydroxylase (CYP11B1), a critical enzyme for cortisol synthesis. Previous studies have reported a number of CYP11B2 inhibitors, most of which have an imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2; however, highly selective inhibitors of human CYP11B2 are still needed. To expand the selectivity in humans, we explored alternative templates and found that pyrazoles were suitable templates for CYP11B2 inhibitors. Investigation of pyrazoles, especially N-alkyl pyrazoles, as a new template to coordinate the heme-iron motif led to a potent and highly selective CYP11B2 inhibitor 28 with an aldosterone-lowering effect at 1 mg/kg dosing in cynomolgus monkeys.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Sakakibara R,Sasaki W,Onda Y,Yamaguchi M,Ushirogochi H,Hiraga Y,Sato K,Nishio M,Egi Y,Takedomi K,Shimizu H,Ohbora T,Akahoshi F

doi

10.1021/acs.jmedchem.8b00328

subject

Has Abstract

pub_date

2018-07-12 00:00:00

pages

5594-5608

issue

13

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S).

    abstract：:Tertiary EGFRC797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFRL858R/T790M/C797S inhibitors. A representative compound, 8r-B,...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b00576

    authors： Shen J,Zhang T,Zhu SJ,Sun M,Tong L,Lai M,Zhang R,Xu W,Wu R,Ding J,Yun CH,Xie H,Lu X,Ding K

    更新日期：2019-08-08 00:00:00

  • Tyrphostins. 3. Structure-activity relationship studies of alpha-substituted benzylidenemalononitrile 5-S-aryltyrphostins.

    abstract：:In this study we describe an extension of our previous studies on cis-benzylidenemalononitrile tyrphostins. We have introduced S-aryl substituents in the 5 position (meta vis-a-vis the malononitrile moiety). We find that these compounds are potent blockers of EGFR kinase and its homolog HER-2 kinase. Interestingly, we...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00075a010

    authors： Gazit A,Osherov N,Posner I,Bar-Sinai A,Gilon C,Levitzki A

    更新日期：1993-11-12 00:00:00

  • Measuring molecular similarity and diversity: total pharmacophore diversity.

    abstract：:A novel method, total pharmacophore diversity (ToPD), based on known pharmacophore features for numerically defining molecular similarity or diversity is described. The method captures the 3D shape and functionality of molecules by the analysis of relevant intramolecular distances to generate a short and descriptive p...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm010036h

    authors： Makara GM

    更新日期：2001-10-25 00:00:00

  • Antiarrhythmic agents. 2-, 3-, And 4-substituted benzylamines.

    abstract：:The synthesis of a series of 2-, 3-, and 4-substituted benzylamine derivatives is described. These compounds were studied for their effect on experimental cardiac arrhythmias. Many of the derivatives, but in particular 2-(p-methoxyphenylethynyl)benzylamine (3d), alpha,alpha-dimethyl-4y(phenylethynyl)benzylamine (7a), ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00236a006

    authors： Remy DC,Van Saun WA Jr,Engelhardt EL

    更新日期：1975-02-01 00:00:00

  • N-substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines are opioid receptor pure antagonists.

    abstract：:N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations w...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm058261c

    authors： Carroll FI,Chaudhari S,Thomas JB,Mascarella SW,Gigstad KM,Deschamps J,Navarro HA

    更新日期：2005-12-29 00:00:00

  • beta-Carbolines as benzodiazepine receptor ligands. 1. Synthesis and benzodiazepine receptor interaction of esters of beta-carboline-3-carboxylic acid.

    abstract：:Several esters of beta-carboline-3-carboxylic acid were synthesized and tested in respect to their affinity for the benzodiazepine receptor in bovine cortex membranes. Out of these derivatives, the methyl, ethyl, and n-propyl ester were clearly the most potent, while the n-butyl, benzyl, and 3-pyridylmethyl ester were...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00358a008

    authors： Lippke KP,Schunack WG,Wenning W,Müller WE

    更新日期：1983-04-01 00:00:00

  • N-n-Propyl-substituted 3-(dimethylphenyl)piperidines display novel discriminative properties between dopamine receptor subtypes: synthesis and receptor binding studies.

    abstract：:3-Phenylpiperidines (PPEs) have been thoroughly investigated in view of their interesting dopaminergic activity, and the N-n-propyl substitution has been suggested as the most effective among several PPEs differently substituted on the phenyl ring. In previous studies, we found that the dimethyl substitution on the ph...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9708700

    authors： Cervetto L,Demontis GC,Giannaccini G,Longoni B,Macchia B,Macchia M,Martinelli A,Orlandini E

    更新日期：1998-12-03 00:00:00

  • The experimental uncertainty of heterogeneous public K(i) data.

    abstract：:The maximum achievable accuracy of in silico models depends on the quality of the experimental data. Consequently, experimental uncertainty defines a natural upper limit to the predictive performance possible. Models that yield errors smaller than the experimental uncertainty are necessarily overtrained. A reliable es...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm300131x

    authors： Kramer C,Kalliokoski T,Gedeck P,Vulpetti A

    更新日期：2012-06-14 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

  • Novel selective PDE4 inhibitors. 3. In vivo antiinflammatory activity of a new series of N-substituted cis-tetra- and cis-hexahydrophthalazinones.

    abstract：:The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC(50) = 8.6-9.4). The N-cycloheptyl- a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0110340

    authors： Van der Mey M,Boss H,Hatzelmann A,Van der Laan IJ,Sterk GJ,Timmerman H

    更新日期：2002-06-06 00:00:00

  • Gadolinium complex of DO3A-benzothiazole aniline (BTA) conjugate as a theranostic agent.

    abstract：:A gadolinium complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and benzothiazole-aniline (BTA) of the type [Gd(DO3A-BTA)(H2O)] has been prepared for use as a single molecule theranostic agent. The kinetic inertness and r1 relaxivity (= 3.84 mM(-1) s(-1)) of the complex compare well with those of s...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm401206t

    authors： Kim HK,Kang MK,Jung KH,Kang SH,Kim YH,Jung JC,Lee GH,Chang Y,Kim TJ

    更新日期：2013-10-24 00:00:00

  • A simple litmus test for aldehyde oxidase metabolism of heteroarenes.

    abstract：:The bioavailability of aromatic azaheterocyclic drugs can be affected by the activity of aldehyde oxidase (AO). Susceptibility to AO metabolism is difficult to predict computationally and can be complicated in vivo by differences between species. Here we report the use of bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm4017976

    authors： O'Hara F,Burns AC,Collins MR,Dalvie D,Ornelas MA,Vaz AD,Fujiwara Y,Baran PS

    更新日期：2014-02-27 00:00:00

  • Identification and prediction of promiscuous aggregating inhibitors among known drugs.

    abstract：:Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzym...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm030191r

    authors： Seidler J,McGovern SL,Doman TN,Shoichet BK

    更新日期：2003-10-09 00:00:00

  • Amino acid modified xanthone derivatives: novel, highly promising membrane-active antimicrobials for multidrug-resistant Gram-positive bacterial infections.

    abstract：:Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compoun...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm501285x

    authors： Koh JJ,Lin S,Aung TT,Lim F,Zou H,Bai Y,Li J,Lin H,Pang LM,Koh WL,Salleh SM,Lakshminarayanan R,Zhou L,Qiu S,Pervushin K,Verma C,Tan DT,Cao D,Liu S,Beuerman RW

    更新日期：2015-01-22 00:00:00

  • Discovery of ligands for ADP-ribosyltransferases via docking-based virtual screening.

    abstract：:The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyzes the transfer of ADP-ribose units onto substrate proteins by using nicotinamide adenine dinucleotide (NAD(+)) as a cosubstrate. They have a documented role in chromatin remodelling and DNA repair, and inhibitors of ARTD1 and 2...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm300746d

    authors： Andersson CD,Karlberg T,Ekblad T,Lindgren AE,Thorsell AG,Spjut S,Uciechowska U,Niemiec MS,Wittung-Stafshede P,Weigelt J,Elofsson M,Schüler H,Linusson A

    更新日期：2012-09-13 00:00:00

  • Controlled oxygen release from pyridone endoperoxides promotes cell survival under anoxic conditions.

    abstract：:In tissue engineering, survival of larger constructs remains challenging due to limited supply of oxygen caused by a lack of early vascularization. Controlled release of oxygen from small organic molecules represents a possible strategy to prevent cell death under anoxic conditions. A comprehensive study of methylated...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm4016137

    authors： Benz S,Nötzli S,Siegel JS,Eberli D,Jessen HJ

    更新日期：2013-12-27 00:00:00

  • Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.

    abstract：:Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerati...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm4000984

    authors： Huang H,Li H,Martásek P,Roman LJ,Poulos TL,Silverman RB

    更新日期：2013-04-11 00:00:00

  • Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.

    abstract：:A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocryst...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b00439

    authors： Bryan MC,Drobnick J,Gobbi A,Kolesnikov A,Chen Y,Rajapaksa N,Ndubaku C,Feng J,Chang W,Francis R,Yu C,Choo EF,DeMent K,Ran Y,An L,Emson C,Huang Z,Sujatha-Bhaskar S,Brightbill H,DiPasquale A,Maher J,Wai J,McKenzi

    更新日期：2019-07-11 00:00:00

  • Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants.

    abstract：:Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology betwe...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm049701n

    authors： Breitenlechner CB,Friebe WG,Brunet E,Werner G,Graul K,Thomas U,Künkele KP,Schäfer W,Gassel M,Bossemeyer D,Huber R,Engh RA,Masjost B

    更新日期：2005-01-13 00:00:00

  • Multivariate analysis and quantitative structure-activity relationships. Inhibition of dihydrofolate reductase and thymidylate synthetase by quinazolines.

    abstract：:Quantitative structure-activity relationships (QSAR) have been established for the inhibition of dihydrofolate reductase and thymidylate synthetase by 2,4-diaminoquinazoline-glutamic acid analogues. For dihydrofolate reductase from both human acute lymphocytic leukemia cells and murine L1210R cells, QSAR's obtained wi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00191a005

    authors： Chen BK,Horváth C,Bertino JR

    更新日期：1979-05-01 00:00:00

  • Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and

    abstract：:Two novel analogues, N-[2-amino-4-ethyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (2) and N-[2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (4), were designed and synthesized as potent dual inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DH...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0203534

    authors： Gangjee A,Yu J,Kisliuk RL,Haile WH,Sobrero G,McGuire JJ

    更新日期：2003-02-13 00:00:00

  • Design, synthesis, and correlation analysis of 7-substituted 4-hydroxyquinoline-3-carboxylic acids as inhibitors of cellular respiration.

    abstract：:Fifteen 7-substituted 4-hydroxyquinoline-3-carboxylic acids have been designed to minimize covariance between the physicochemical substituent parameters: pi, MR, and sigmap. The molecules have been synthesized and evaluated for their ability to inhibit the respiration of Ehrlich ascites cells as a whole cell model and...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00218a003

    authors： Shah KJ,Coats EA

    更新日期：1977-08-01 00:00:00

  • Lipolanthionine peptides act as inhibitors of TLR2-mediated IL-8 secretion. Synthesis and structure-activity relationships.

    abstract：:Lipoproteins from gram-positive and -negative bacteria, mycoplasma, and shorter synthetic lipopeptide analogues activate cells of the innate immune system via the Toll-like receptor TLR2/TLR1 or TLR2/TLR6 heterodimers. For this reason, these compounds constitute highly active adjuvants for vaccines either admixed or c...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm050585d

    authors： Seyberth T,Voss S,Brock R,Wiesmüller KH,Jung G

    更新日期：2006-03-09 00:00:00

  • Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025).

    abstract：:A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm500951r

    authors： Ivachtchenko AV,Mitkin OD,Yamanushkin PM,Kuznetsova IV,Bulanova EA,Shevkun NA,Koryakova AG,Karapetian RN,Bichko VV,Trifelenkov AS,Kravchenko DV,Vostokova NV,Veselov MS,Chufarova NV,Ivanenkov YA

    更新日期：2014-09-25 00:00:00

  • Distamycin analogues with enhanced lipophilicity: synthesis and antimicrobial activity.

    abstract：:Forty-eight heterocyclic amino acid trimers, analogues of distamycin, with a number of features that enhance lipophilicity are described. They contain alkyl or cycloalkyl groups larger than methyl; some are N-terminated by acetamide or methoxybenzamide and are C-terminated by dimethylaminopropyl or aliphatic heterocyl...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm031089x

    authors： Khalaf AI,Waigh RD,Drummond AJ,Pringle B,McGroarty I,Skellern GG,Suckling CJ

    更新日期：2004-04-08 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

  • Single point D-substituted corticotropin-releasing factor analogues: effects on potency and physicochemical characteristics.

    abstract：:In an attempt to determine which conformational parameters are important for the biological activity of ovine corticotropin-releasing factor (oCRF), we have synthesized in significant amounts (50-200 mg) and characterized chemically, structurally (CD), and biologically, oCRF analogues with substitution of each amino a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00072a003

    authors： Rivier J,Rivier C,Galyean R,Miranda A,Miller C,Craig AG,Yamamoto G,Brown M,Vale W

    更新日期：1993-10-01 00:00:00

  • Feature selection for structure-activity correlation using binary particle swarms.

    abstract：:We present a new feature selection algorithm for structure-activity and structure-property correlation based on particle swarms. Particle swarms explore the search space through a population of individuals that adapt by returning stochastically toward previously successful regions, influenced by the success of their n...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0104668

    authors： Agrafiotis DK,Cedeño W

    更新日期：2002-02-28 00:00:00

  • Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC): Optimization through Iterative Rational Drug Design.

    abstract：:The F9/Yde/Fml pilus, tipped with the FmlH adhesin, has been shown to provide uropathogenic Escherichia coli (UPEC) a fitness advantage in urinary tract infections (UTIs). Here, we used X-ray structure guided design to optimize our previously described ortho-biphenyl Gal and GalNAc FmlH antagonists such as compound 1 ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b01561

    authors： Maddirala AR,Klein R,Pinkner JS,Kalas V,Hultgren SJ,Janetka JW

    更新日期：2019-01-24 00:00:00

  • (E)-3-[[[[6-(2-carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]-methyl]thio]methyl]benzoic acid and related compounds: high affinity leukotriene B4 receptor antagonists.

    abstract：:(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The p...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00046a017

    authors： Daines RA,Chambers PA,Eggleston DS,Foley JJ,Griswold DE,Haltiwanger RC,Jakas DR,Kingsbury WD,Martin LD,Pendrak I

    更新日期：1994-09-30 00:00:00