Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist (MABA) dual pharmacology molecules.


:We sought to design dual pharmacology bronchodilators targeting both the M(3) muscarinic acetylcholine and beta-2 adrenergic (β(2)) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptors.


Bioorg Med Chem Lett


Hughes AD,Chin KH,Dunham SL,Jasper JR,King KE,Lee TW,Mammen M,Martin J,Steinfeld T




Has Abstract


2011-03-01 00:00:00














  • Inhibition of mandelate racemase by the substrate-intermediate-product analogue 1,1-diphenyl-1-hydroxymethylphosphonate.

    abstract::Mandelate racemase has been studied as a paradigm for enzyme-catalyzed abstraction of a proton from carbon acids with relatively high pKa values. 1,1-Diphenyl-1-hydroxymethylphosphonate is a substrate-intermediate-product analogue and is a modest competitive inhibitor of the enzyme (Ki=1.41+/-0.09 mM), suggesting that...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Burley RK,Bearne SL

    更新日期:2005-10-01 00:00:00

  • Use of gamma-aminopropyl-coated glass surface for the patterning of oligonucleotides through oxime bond formation.

    abstract::The present work reports on the preparation of glass surfaces coated with NPPOC-protected aminooxy groups and their use for the patterning of oligonucleotides on glass slides and in capillary tubes. The method involves the use of surfaces coated with amino groups using (gamma-aminopropyl)triethoxy silane and subsequen...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Dendane N,Hoang A,Defrancq E,Vinet F,Dumy P

    更新日期:2008-04-15 00:00:00

  • Molecular basis for cis-urocanic acid as a 5-HT(2A) receptor agonist.

    abstract::The underlying mechanisms of urocanic acid (UA) to induce immune suppression remain elusive until the recent finding that cis-UA acts via the serotonin, 5-hydroxytryptamine (5-HT) receptor subtype 5-HT(2A). In the present study, the interactions of cis-UA to 5-HT(2A) receptor were explored and compared with those of 5...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Shen L,Ji HF

    更新日期:2009-09-15 00:00:00

  • Substituted aminobenzimidazole pyrimidines as cyclin-dependent kinase inhibitors.

    abstract::A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity against CDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in the CDK1 assay (IC(50)<10nM). Cell cycle analysis showed that the compounds...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Verma S,Nagarathnam D,Shao J,Zhang L,Zhao J,Wang Y,Li T,Mull E,Enyedy I,Wang C,Zhu Q,Altieri M,Jordan J,Dang TT,Reddy S

    更新日期:2005-04-15 00:00:00

  • Potent and selective oxytocin receptor agonists without disulfide bridges.

    abstract::Oxytocin (OT) is a neuropeptide involved in a wide variety of physiological actions, both peripherally and centrally. Many human studies have revealed the potential of OT to treat autism spectrum disorders and schizophrenia. OT interacts with the OT receptor (OTR) as well as vasopressin 1a and 1b receptors (V1aR, V1bR...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Adachi Y,Sakimura K,Shimizu Y,Nakayama M,Terao Y,Yano T,Asami T

    更新日期:2017-06-01 00:00:00

  • Discovery of potent, selective small molecule inhibitors of α-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIα).

    abstract::The discovery and optimisation of novel, potent and selective small molecule inhibitors of the α-isoform of type III phosphatidylinositol-4-kinase (PI4Kα) are described. Lead compounds show cellular activity consistent with their PI4Kα potency inhibiting the accumulation of IP1 after PDGF stimulation and reducing cell...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Raubo P,Andrews DM,McKelvie JC,Robb GR,Smith JM,Swarbrick ME,Waring MJ

    更新日期:2015-08-15 00:00:00

  • Powerful probes for glycosidases: novel, fluorescently tagged glycosidase inhibitors.

    abstract::Amino-1,2,5-trideoxy-2,5-imino-D-mannitol was fluorescently tagged by reaction with dansyl chloride at N-1 or by attachment of a dansyl amide bearing spacer to this centre. Compounds obtained are highly potent inhibitors of beta-glucosidase exhibiting Ki values in the single figure nanomolar range. The 1-N-dansyl subs...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hermetter A,Scholze H,Stütz AE,Withers SG,Wrodnigg TM

    更新日期:2001-05-21 00:00:00

  • Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors.

    abstract::We report the design, synthesis, and structure-activity relationship (SAR) of a series of novel pyrido[2,3-d]pyrimidin-7-one compounds as potent Abl kinase inhibitors. We evaluate their specificity profile against a panel of human recombinant kinases, as well as their biological profile toward a panel of well-characte...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Antczak C,Veach DR,Ramirez CN,Minchenko MA,Shum D,Calder PA,Frattini MG,Clarkson B,Djaballah H

    更新日期:2009-12-15 00:00:00

  • Uridine phosphorylase inhibitors: chemical modification of benzyloxybenzyl-barbituric acid and its effects on urdpase inhibition.

    abstract::5-(o-Benzyloxy)benzylbarbituric acid (6) and 5-(p-benzyloxy)benzylbarbituric acid (7) were prepared and their inhibitory activities compared to 5-(m-benzyloxy)-benzylbarbituric acid (BBB) a known, potent inhibitor of uridine phosphorylase (UrdPase). Compounds 6 and 7 were 18-fold and 51-fold less active, respectively,...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Guerin DJ,Mazeas D,Musale MS,Naguib FN,Al Safarjalani ON,el Kouni MH,Panzica RP

    更新日期:1999-06-07 00:00:00

  • Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.

    abstract::This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (~10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple 'molecular swit...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wen W,Wu W,Romaine IM,Kaufmann K,Du Y,Sulikowski GA,Weaver CD,Lindsley CW

    更新日期:2013-08-15 00:00:00

  • An efficient synthesis of [1,3]dioxolo[4,5-g]thieno[3,4-b]quinolin-8(5H)-ones as novel thiazapodophyllotoxin analogues with potential anticancer activity.

    abstract::A catalyst-free synthesis of 6,9-dihydro-[1,3]dioxolo[4,5-g]thieno[3,4-b]quinolin-8(5H)-ones as novel analogues of podophyllotoxins was developed by a three-component reaction of aldehydes, ethyl 2,4-dioxotetrahydrothiophene-3-carboxylate and 3,4-(methylenedioxy)aniline. This methodology not only provides new chemical...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li T,Lu T,Yu C,Yao C

    更新日期:2015-04-01 00:00:00

  • Structural and stereochemical requirements of the spiroketal group of hippuristanol for antiproliferative activity.

    abstract::Hippuristanol is a natural product that has recently been shown to inhibit eukaryotic translation initiation and tumor cell proliferation. To investigate the structure and activity relationship of hippuristanol, we synthesized a series of analogs by expanding the size of its F ring and determined their effects on the ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li W,Dang Y,Liu JO,Yu B

    更新日期:2010-05-15 00:00:00

  • Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols.

    abstract::A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kim CY,Mahaney PE,McConnell O,Zhang Y,Manas E,Ho DM,Deecher DC,Trybulski EJ

    更新日期:2009-09-01 00:00:00

  • Symmetric adamantyl-diureas as soluble epoxide hydrolase inhibitors.

    abstract::A series of inhibitors of the soluble epoxide hydrolase (sEH) containing two urea groups has been developed. Inhibition potency of the described compounds ranges from 2.0 μM to 0.4 nM. 1,6-(Hexamethylene)bis[(adamant-1-yl)urea] (3b) was found to be a potent slow tight binding inhibitor (IC50=0.5 nM) with a strong bind...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Burmistrov V,Morisseau C,Lee KS,Shihadih DS,Harris TR,Butov GM,Hammock BD

    更新日期:2014-05-01 00:00:00

  • Conversion of human-selective PPARalpha agonists to human/mouse dual agonists: a molecular modeling analysis.

    abstract::To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxa...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang M,Winneroski LL,Ardecky RJ,Babine RE,Brooks DA,Etgen GJ,Hutchison DR,Kauffman RF,Kunkel A,Mais DE,Montrose-Rafizadeh C,Ogilvie KM,Oldham BA,Peters MK,Rito CJ,Rungta DK,Tripp AE,Wilson SB,Xu Y,Zink RW,McCarthy

    更新日期:2004-12-20 00:00:00

  • 1,2,3-Triazole fused with pyridine/pyrimidine as new template for antimicrobial agents: Regioselective synthesis and identification of potent N-heteroarenes.

    abstract::The 1,2,3-triazole ring fused with pyridine/pyrimidine was explored as new template for the identification of potential antimicrobial agents. The regioselective synthesis of these pre-designed N-heteroarenes was achieved via exploring the application of Buchwald's strategy (i.e. C-N bond formation/reduction/diazotizat...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Marepu N,Yeturu S,Pal M

    更新日期:2018-11-01 00:00:00

  • Transformation of 8-prenylnaringenin by Absidia coerulea and Beauveria bassiana.

    abstract::Beauveria bassiana AM278 and Absidia coerulea AM93 converted 8-prenylnaringenin (1) into two glycoside derivatives (7-O-β-D-glucopyranoside) (2) and 7-O-β-D-4'''-O-methylglucopyranoside) (3) in high yields in processes conducted in Saboraud medium. 8-Prenylnaringenin 7-O-β-D-4'''-O-methylglucopyranoside (3) is a new c...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bartmańska A,Tronina T,Huszcza E

    更新日期:2012-10-15 00:00:00

  • Methoxychalcone inhibitors of androgen receptor translocation and function.

    abstract::Androgen receptor activity drives incurable castrate-resistant prostate cancer. All approved antiandrogens inhibit androgen receptor-driven transcription, and in addition the second-generation antiandrogen MDV3100 inhibits ligand-activated androgen receptor nuclear translocation, via an unknown mechanism. Here, we rep...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kim YS,Kumar V,Lee S,Iwai A,Neckers L,Malhotra SV,Trepel JB

    更新日期:2012-03-01 00:00:00

  • Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis.

    abstract::A class of small molecules displaying comparable activities with peptide ligands BAM22 and corticostatin-14 at both the human and rhesus monkey MrgX1 and MrgX2 receptors, respectively, was discovered. A comparative study to compare solid-phase and solution-phase chemistries for the efficient synthesis of the active cl...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Malik L,Kelly NM,Ma JN,Currier EA,Burstein ES,Olsson R

    更新日期:2009-03-15 00:00:00

  • Structure-activity relationships amongst 4-position quinoline methanol antimalarials that inhibit the growth of drug sensitive and resistant strains of Plasmodium falciparum.

    abstract::Utilizing mefloquine as a scaffold, a next generation quinoline methanol (NGQM) library was constructed to identify early lead compounds that possess biological properties consistent with the target product profile for malaria chemoprophylaxis while reducing permeability across the blood-brain barrier. The library of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Milner E,McCalmont W,Bhonsle J,Caridha D,Carroll D,Gardner S,Gerena L,Gettayacamin M,Lanteri C,Luong T,Melendez V,Moon J,Roncal N,Sousa J,Tungtaeng A,Wipf P,Dow G

    更新日期:2010-02-15 00:00:00

  • Sequential cytotoxicity: a theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids.

    abstract::The concept of sequential cytotoxicity, which states that successive chemical attacks on cellular constituents can be more deleterious to neoplasms than normal cells, was evaluated using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines 1 and related phosphonic acids 2, which were screened against a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Das S,Das U,Sakagami H,Hashimoto K,Kawase M,Gorecki DK,Dimmock JR

    更新日期:2010-11-15 00:00:00

  • Selective alpha1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones.

    abstract::A series of alpha1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in the low nanomolar to picomolar range along with high selectivity was obtained. In vivo efficacy in a prostate contraction model in rats was observed with a few derivatives. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nantermet PG,Barrow JC,Selnick HG,Homnick CF,Freidinger RM,Chang RS,O'Malley SS,Reiss DR,Broten TP,Ransom RW,Pettibone DJ,Olah T,Forray C

    更新日期:2000-08-07 00:00:00

  • Design, synthesis, biological evaluation and molecular modeling of dihydropyrazole sulfonamide derivatives as potential COX-1/COX-2 inhibitors.

    abstract::Novel dihydropyrazole sulfonamide derivatives (30-56) were designed, synthesized, and evaluated for their biological activities as COX-1 and COX-2 inhibitors. In vitro biological evaluation against three human tumor cell lines revealed that most target compounds showed antiproliferative activities. Among the compounds...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chen Z,Wang ZC,Yan XQ,Wang PF,Lu XY,Chen LW,Zhu HL,Zhang HW

    更新日期:2015-05-01 00:00:00

  • Serendipitous discovery of aryl boronic acids as β-lactamase inhibitors.

    abstract::High throughput screening for β-lactamase inhibitors afforded biphenyl hits such as 1. Hit confirmation and X-ray soaking experiments with Pseudomonas Aeruginosa AmpC enzyme led to the identification of an aryl boronic acid-serine complex 4, which was formed from phenyl boronic acid 8 (an impurity in compound 1) and e...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yang SW,Pan J,Root Y,Scapin G,Xiao L,Su J

    更新日期:2020-01-15 00:00:00

  • Synthesis of some novel phosphorylated and thiophosphorylated benzimidazoles and benzothiazoles and their evaluation for larvicidal potential to Aedes albopictus and Culex quinquefasciatus.

    abstract::Series of benzimidazole and benzothiazole linked phosphoramidates and phosphoramidothioates (5a-j) and benzimidazole linked phenylphosphoramidates and phenylphosphoramidothioates (10a-e) were synthesized. The title compounds were preliminary screened for mosquito larvicidal properties against Aedes albopictus and Cule...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bandyopadhyay P,Sathe M,Tikar SN,Yadav R,Sharma P,Kumar A,Kaushik MP

    更新日期:2014-07-01 00:00:00

  • Design and synthesis of tetracyclic nonpeptidic biaryl nitrile inhibitors of cathepsin K.

    abstract::The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Setti EL,Venkatraman S,Palmer JT,Xie X,Cheung H,Yu W,Wesolowski G,Robichaud J

    更新日期:2006-08-15 00:00:00

  • Optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of HIV capsid assembly inhibitors 2: structure-activity relationships (SAR) of the C3-phenyl moiety.

    abstract::Detailed structure-activity relationships of the C3-phenyl moiety that allow for the optimization of antiviral potency of a series of 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione inhibitors of HIV capsid (CA) assembly are described. Combination of favorable substitutions gave additive SAR and allowed for the identifica...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fader LD,Landry S,Goulet S,Morin S,Kawai SH,Bousquet Y,Dion I,Hucke O,Goudreau N,Lemke CT,Rancourt J,Bonneau P,Titolo S,Amad M,Garneau M,Duan J,Mason S,Simoneau B

    更新日期:2013-06-01 00:00:00

  • Synthesis and antifungal activities of new fluconazole analogues with azaheterocycle moiety.

    abstract::A series of fluconazole analogues 5-20 incorporating azaindole and indole moieties were prepared using oxirane intermediates synthesized under microwave irradiation. All of the compounds were evaluated in vitro against two clinically important fungi, Candida albicans and Aspergillus fumigatus. Four derivatives 6, 13, ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lebouvier N,Pagniez F,Duflos M,Le Pape P,Na YM,Le Baut G,Le Borgne M

    更新日期:2007-07-01 00:00:00

  • Preparation of 5'-deoxy-5'-amino-5'-C-methyl adenosine derivatives and their activity against DOT1L.

    abstract::From a readily available 5-C-Me ribofuranoside, we have realized a reliable route to valuable 5'-deoxy-5'-amino-5'-C-methyl adenosine derivatives at gram scale with confirmed stereochemistry. These adenosine derivatives are useful starting materials for the preparation of 5'-deoxy-5'-amino-5'-C-methyl adenosine deriva...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu T,Xie W,Li C,Ren H,Mao Y,Chen G,Cheng M,Zhao D,Shen J,Li J,Zhou Y,Xiong B,Chen YL

    更新日期:2017-11-15 00:00:00

  • Synthesis of camphecene derivatives using click chemistry methodology and study of their antiviral activity.

    abstract::A series of seventeen tetrazole derivatives of 1,7,7-trimethyl-[2.2.1]bicycloheptane were synthesized using click chemistry methodology and characterized by spectral data. Studies of cytotoxicity and in vitro antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells of the compounds obtained w...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Artyushin OI,Sharova EV,Vinogradova NM,Genkina GK,Moiseeva AA,Klemenkova ZS,Orshanskaya IR,Shtro AA,Kadyrova RA,Zarubaev VV,Yarovaya OI,Salakhutdinov NF,Brel VK

    更新日期:2017-05-15 00:00:00