当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X(3)/P2X(2/3) antagonist for the treatment of pain.

Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X(3)/P2X(2/3) antagonist for the treatment of pain.

Abstract：

:P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X(3) and P2X(2/3) receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X(3)/P2X(2/3) antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X(3)/P2X(2/3) antagonist.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Carter DS,Alam M,Cai H,Dillon MP,Ford AP,Gever JR,Jahangir A,Lin C,Moore AG,Wagner PJ,Zhai Y

doi

10.1016/j.bmcl.2009.02.003

subject

Has Abstract

pub_date

2009-03-15 00:00:00

pages

1628-31

issue

6

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(09)00145-0

journal_volume

19

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS文献大全
  • Inhibition of amyloid fibril formation and cytotoxicity by caffeic acid-conjugated amyloid-β C-terminal peptides.

    abstract：:Amyloid-β (Aβ) deposition and oxidative stress observed in the brains of patients with Alzheimer's disease (AD) are important targets for therapeutic intervention. In this study, we conjugated the antioxidants caffeic acid (CA) and dihydrocaffeic acid (DHCA) to Aβ1-42 C-terminal motifs (Aβx-42: x=38, 40) to synthesize...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.10.027

    authors： Arai T,Ohno A,Mori K,Kuwata H,Mizuno M,Imai K,Hara S,Shibanuma M,Kurihara M,Miyata N,Nakagawa H,Fukuhara K

    更新日期：2016-11-15 00:00:00

  • A hit deconstruction approach for the discovery of fetal hemoglobin inducers.

    abstract：:Beta-hemoglobinopathies such as sickle cell disease represent a major global unmet medical need. De-repression of fetal hemoglobin in erythrocytes is a clinically validated approach for the management of sickle cell disease, but the only FDA-approved medicine for this purpose has limitations to its use. We conducted a...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2018.10.032

    authors： Benowitz AB,Eberl HC,Erickson-Miller CL,Gilmartin AG,Gore ER,Montoute MN,Wu Z

    更新日期：2018-12-15 00:00:00

  • Hydroxamic acid based histone deacetylase inhibitors with confirmed activity against the malaria parasite.

    abstract：:Recent studies have highlighted a key role in regulating gene transcription, in both eukaryotes and prokaryotes, by enzymes that control the acetylation and deacetylation of histones. In particular, inhibitors of histone deacetylases (HDAC-Is) have been shown effective in controlling the development of many parasites,...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2014.12.051

    authors： Giannini G,Battistuzzi G,Vignola D

    更新日期：2015-02-01 00:00:00

  • Heterobiaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part II.

    abstract：:C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivative...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.10.011

    authors： Trova MP,Barnes KD,Alicea L,Benanti T,Bielaska M,Bilotta J,Bliss B,Duong TN,Haydar S,Herr RJ,Hui Y,Johnson M,Lehman JM,Peace D,Rainka M,Snider P,Salamone S,Tregay S,Zheng X,Friedrich TD

    更新日期：2009-12-01 00:00:00

  • Porphyrins containing nitric oxide donors: Synthesis and cancer cell-oriented NO release.

    abstract：:Four novel porphyrins containing nitric oxide (NO) donors were synthesized, and the structures of all the products were characterized by IR, UV-vis, (1)H NMR, and elementary analysis. Interestingly, these new compounds not only were able to release NO, but also showed cancer cell-oriented accumulation. Higher accumula...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.02.005

    authors： Liu W,Liu C,Gong C,Lin W,Guo C

    更新日期：2009-03-15 00:00:00

  • Synthesis and antimicrobial activity of beta-lactam-bile acid conjugates linked via triazole.

    abstract：:Synthesis of novel 1,2,3-triazole-linked beta-lactam-bile acid conjugates 17-24 using 1,3-dipolar cycloaddition reaction of azido beta-lactam and terminal alkyne of bile acids in the presence of Cu(I) catalyst (click chemistry) have been realized. These molecules were evaluated in vitro for their antifungal and antiba...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.01.102

    authors： Vatmurge NS,Hazra BG,Pore VS,Shirazi F,Chavan PS,Deshpande MV

    更新日期：2008-03-15 00:00:00

  • Synthesis and structure-activity relationships of oxime neurokinin antagonists: discovery of potent arylamides.

    abstract：:The structural modification of the benzylic ether region of oxime 1 has resulted in the identification of several novel aryl amides as selective or dual NK(1)/NK(2) antagonists. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00709-0

    authors： Shih NY,Albanese M,Anthes JC,Carruthers NI,Grice CA,Lin L,Mangiaracina P,Reichard GA,Schwerdt J,Seidl V,Wong SC,Piwinski JJ

    更新日期：2002-01-21 00:00:00

  • Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists.

    abstract：:Despite the excellent in vitro potency of a series of benzamide glycoprotein IIb/IIIa antagonists, which have been reported previously, poor in vivo potency in the inhibition of platelet aggregation was observed when the most potent inhibitor XU057 was dosed intravenously to dogs. In this communication, we report that...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(98)00637-4

    authors： Xue CB,Roderick J,Mousa S,Olson RE,DeGrado WF

    更新日期：1998-12-15 00:00:00

  • Structure-activity relationship in two series of aminoalkyl substituted coumarin inhibitors of gyrase B.

    abstract：:Two series of aminosubstituted coumarins were synthesised and evaluated in vitro as inhibitors of DNA gyrase and as potential antibacterials. Novel novobiocin-like coumarins, 4-(dialkylamino)methylcoumarins and 4-((2-alkylamino)ethoxy)coumarins, were discovered as gyrase B inhibitors with promising antibacterial activ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(99)00492-8

    authors： Laurin P,Ferroud D,Schio L,Klich M,Dupuis-Hamelin C,Mauvais P,Lassaigne P,Bonnefoy A,Musicki B

    更新日期：1999-10-04 00:00:00

  • Oxidative calcium release from catechol.

    abstract：:Oxidation of 4-methylcatechol previously exposed to aqueous calcium chloride was shown by ion chromatography to be associated with release of calcium ions. The catechol was oxidised to the corresponding orthoquinone by the use of tyrosinase from Agaricus bisporus. The oxidative release of calcium from the catechol is ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2015.02.036

    authors： Riley PA,Stratford MR

    更新日期：2015-04-01 00:00:00

  • Interactions of N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-3-aryl-2-yl-ureas with dopamine D2 and 5-hydroxytryptamine 5HT(1A) receptors.

    abstract：:It is suggested that the ratio of dopamine D(2) to 5-hydroxytryptamine 5-HT(1A) activity is an important parameter that determines the efficiency of antipsychotic drugs. Here we present the synthesis of N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phe...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.04.098

    authors： Sukalovic V,Ignjatovic D,Tovilovic G,Andric D,Shakib K,Kostic-Rajacic S,Soskic V

    更新日期：2012-06-15 00:00:00

  • The synthesis of pteroyl-lys conjugates and its application as Technetium-99m labeled radiotracer for folate receptor-positive tumor targeting.

    abstract：:Aiming to develop a new (99m)Tc-labeled folate derivative for FR-positive tumor imaging, a simpler method has been established to synthesize the folate-drug conjugates with free α-carboxyl group. In this study, the conjugate pteroyl-lys-HYNIC was synthesized and labeled with (99m)Tc using tricine and TPPTS as co-ligan...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.02.014

    authors： Guo H,Xie F,Zhu M,Li Y,Yang Z,Wang X,Lu J

    更新日期：2011-04-01 00:00:00

  • Modeling directed design and biological evaluation of quinazolinones as non-peptidic growth hormone secretagogues.

    abstract：:Quinazolinone derivatives were synthesized and evaluated as non-peptidic growth hormone secretagogues. Modeling guided design of quinazolinone compound 21 led to a potency enhancement of greater than 200-fold compared to human growth hormone secretagogue affinity of a screening lead 4. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(99)00584-3

    authors： Ye Z,Gao Y,Bakshi RK,Chen MH,Rohrer SP,Feighner SD,Pong SS,Howard AD,Blake A,Birzin ET,Locco L,Parmar RM,Chan WW,Schaeffer JM,Smith RG,Patchett AA,Nargund RP

    更新日期：2000-01-03 00:00:00

  • Design of selective Cathepsin inhibitors.

    abstract：:A number of molecular recognition features have been exploited in structure-based design of selective Cathepsin inhibitors. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.06.090

    authors： Bethel PA,Gerhardt S,Jones EV,Kenny PW,Karoutchi GI,Morley AD,Oldham K,Rankine N,Augustin M,Krapp S,Simader H,Steinbacher S

    更新日期：2009-08-15 00:00:00

  • Synthesis and molecular modeling studies of 3-chloro-4-substituted-1-(8-hydroxy-quinolin-5-yl)-azetidin-2-ones as novel anti-filarial agents.

    abstract：:A series of 3-chloro-4-substituted-1-(8-hydroxy-quinolin-5-yl)-azetidin-2-ones were synthesized and evaluated for their in vitro anti-filarial activity. To pre-assess the anti-filarial behavior of synthesized compounds (V(a-f)) on a structural basis, automated docking studies were carried out with Molecular Design Sui...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.04.106

    authors： Chhajed SS,Manisha P,Bastikar VA,Animeshchandra H,Ingle VN,Upasani CD,Wazalwar SS

    更新日期：2010-06-15 00:00:00

  • Trityl radicals in perfluorocarbon emulsions as stable, sensitive, and biocompatible oximetry probes.

    abstract：:EPR oximetry with the use of trityl radicals can enable sensitive O2 measurement in biological cells and tissues. However, in vitro cellular and in vivo biological applications are limited by rapid trityl probe degradation or biological clearance and the need to enhance probe O2 sensitivity. We synthesized novel perfl...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.10.066

    authors： Dhimitruka I,Alzarie YA,Hemann C,Samouilov A,Zweier JL

    更新日期：2016-12-01 00:00:00

  • The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2.

    abstract：:Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.01.011

    authors： Han X,Civiello RL,Conway CM,Cook DA,Davis CD,Degnan AP,Jiang XJ,Macci R,Mathias NR,Moench P,Pin SS,Schartman R,Signor LJ,Thalody G,Tora G,Whiterock V,Xu C,Macor JE,Dubowchik GM

    更新日期：2013-03-15 00:00:00

  • Novel antifungals based on 4-substituted imidazole: solid-phase synthesis of substituted aryl sulfonamides towards optimization of in vitro activity.

    abstract：:The in vitro activity of novel 4-substituted imidazole antifungals was optimized by solid-phase chemistry and parallel synthesis. Potent yeast-selective as well as broad-spectrum antifungal compounds (32 and 20) were discovered. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(00)00551-5

    authors： Saha AK,Liu L,Marichal P,Odds F

    更新日期：2000-12-18 00:00:00

  • Double stranded DNA discrimination by di-pyrene modified gamma-cyclodextrin.

    abstract：:Neutral fluorescent active di-pyrene modified gamma-cyclodextrin (1) was synthesized in order to discriminate with single and double strand DNA (ssDNA and dsDNA, respectively) with high selectivity. The binding and selectivity of 1 for dsDNA was indicated by increase of the fluorescent intensity in an addition of dsDN...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.04.066

    authors： Takeda A,Akimoto K,Kondo Y,Hamada F

    更新日期：2010-06-01 00:00:00

  • Design, synthesis, and biological activity of novel purine and bicyclic pyrimidine factor Xa inhibitors.

    abstract：:The synthesis of amidinoaryloxy 9-benzyl-8-methyl-9H-purine, 7,8-dihydropteridine-6(5H)-one and 5,7-dihydropyrimido[4,5-b][1,4]oxazine-6-one inhibitors of Factor Xa is described. These compounds show nanomolar potency against FXa and maintain high selectivity over thrombin and trypsin. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(98)00386-2

    authors： Buckman BO,Mohan R,Koovakkat S,Liang A,Trinh L,Morrissey MM

    更新日期：1998-08-18 00:00:00

  • A highly atom economic, chemo-, regio- and stereoselective synthesis and evaluation of spiro-pyrrolothiazoles as antitubercular agents.

    abstract：:The 1,3-dipolar cycloaddition of azomethine ylides derived from substituted isatins and 1,3-thiazolane-4-carboxylic acid to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones afforded novel spiro-pyrrolothiazoles chemo-, regio- and stereoselectively in quantitative yields. These compounds w...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.10.107

    authors： Karthikeyan SV,Bala BD,Raja VP,Perumal S,Yogeeswari P,Sriram D

    更新日期：2010-01-01 00:00:00

  • Cyclopenta[g]quinazoline-based antifolates: the effect of the chirality at the 6-position on the inhibition of thymidylate synthase (TS).

    abstract：:Cyclopenta[g]quinazoline-based inhibitors of thymidylate synthase (TS) possess a chiral centre at the 6-position of the molecule. The effect of this chirality on the inhibition of TS was investigated by synthesising compounds 6S-1a-c, 6R-1a-c. It was shown, in particular with the diastereoisomers 6S-1c, 6R-1c, that th...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00612-6

    authors： Bavetsias V,Marriott JH,Theti DS,Melin JC,Wilson SC,Jackman AL

    更新日期：2001-12-03 00:00:00

  • Non-peptide alpha(v)beta(3) antagonists: identification of potent, chain-shortened RGD mimetics that incorporate a central pyrrolidinone constraint.

    abstract：:Antagonists of the integrin receptor alpha(v)beta(3) are expected to have utility in the treatment of osteoporosis through inhibition of bone resorption. A series of potent, chain-shortened, pyrrolidinone-containing alpha(v)beta(3) receptor antagonists is described. Two sets of diasteromeric pairs of high-affinity ant...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2003.09.055

    authors： Perkins JJ,Duong LT,Fernandez-Metzler C,Hartman GD,Kimmel DB,Leu CT,Lynch JJ,Prueksaritanont T,Rodan GA,Rodan SB,Duggan ME,Meissner RS

    更新日期：2003-12-15 00:00:00

  • Trithiocarbonates: exploration of a new head group for HDAC inhibitors.

    abstract：:Inhibition of histone deacetylases class I/II enzymes is a new, promising approach for cancer therapy. In the present study, we disclose a new structural class of HDAC inhibitors with the trithiocarbonate motif. A clear structure-activity-relationship was obtained for the cap-linker motif and the putative Zn(2+) compl...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.06.063

    authors： Dehmel F,Ciossek T,Maier T,Weinbrenner S,Schmidt B,Zoche M,Beckers T

    更新日期：2007-09-01 00:00:00

  • Pyrrolo[2,3-d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck.

    abstract：:A series of pyrrolo[2,3-d]pyrimidines was synthesized and evaluated as inhibitors of Lck. Lck accommodates a diverse set of substituents at N-7. Altering the substituent at N-7 provided compound 13, an orally available lck inhibitor which inhibited TCR mediated IL-2 production after oral dosing. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(02)00195-6

    authors： Calderwood DJ,Johnston DN,Munschauer R,Rafferty P

    更新日期：2002-06-17 00:00:00

  • Synthesis and anti-HIV activity of 2'-deoxy-2'-fluoro-4'-C-ethynyl nucleoside analogs.

    abstract：:Based on the favorable antiviral profiles of 4'-substituted nucleosides, novel 1-(2'-deoxy-2'-fluoro-4'-C-ethynyl-beta-D-arabinofuranosyl)-uracil (1a), -thymine (1b), and -cytosine (2) analogs were synthesized. Compounds 1b and 2 exhibited potent anti-HIV-1 activity with IC(50) values of 86 and 1.34 nM, respectively, ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.05.090

    authors： Wang Q,Li Y,Song C,Qian K,Chen CH,Lee KH,Chang J

    更新日期：2010-07-15 00:00:00

  • Radiosynthesis of PET radiotracer as a prodrug for imaging group II metabotropic glutamate receptors in vivo.

    abstract：:Group II metabotropic glutamate receptors (mGluRs) have been implicated in a variety of neurological and psychiatric disorders in recent studies. As a noninvasive medical imaging technique and a powerful tool in neurological research, positron emission tomography (PET) offers the possibility to visualize and study gro...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.01.039

    authors： Wang JQ,Zhang Z,Kuruppu D,Brownell AL

    更新日期：2012-03-01 00:00:00

  • Discovery of novel arylpyrazole series as potent and selective opioid receptor-like 1 (ORL1) antagonists.

    abstract：:The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure-activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.04.116

    authors： Kobayashi K,Uchiyama M,Ito H,Takahashi H,Yoshizumi T,Sakoh H,Nagatomi Y,Asai M,Miyazoe H,Tsujita T,Hirayama M,Ozaki S,Tani T,Ishii Y,Ohta H,Okamoto O

    更新日期：2009-07-01 00:00:00

  • Sulfonamido-derivatives of unsubstituted carbazoles as BACE1 inhibitors.

    abstract：:A novel series of variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylsulfonamides has been synthesized and assayed for β-Secretase (BACE1) inhibitory activity. BACE1 is a widely recognized drug target for the prevention and treatment of Alzheimer's Disease (AD). The introduction of benzyl substituents ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2017.09.058

    authors： Bertini S,Ghilardi E,Asso V,Minutolo F,Rapposelli S,Digiacomo M,Saccomanni G,Salmaso V,Sturlese M,Moro S,Macchia M,Manera C

    更新日期：2017-11-01 00:00:00

  • Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists.

    abstract：:Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.06.055

    authors： Thompson SK,Washburn DG,Frazee JS,Madauss KP,Hoang TH,Lapinski L,Grygielko ET,Glace LE,Trizna W,Williams SP,Duraiswami C,Bray JD,Laping NJ

    更新日期：2009-08-15 00:00:00