Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors.


:Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.


Bioorg Med Chem Lett


Fidanze SD,Liu D,Mantei RA,Hasvold LA,Pratt JK,Sheppard GS,Wang L,Holms JH,Dai Y,Aguirre A,Bogdan A,Dietrich JD,Marjanovic J,Park CH,Hutchins CW,Lin X,Bui MH,Huang X,Wilcox D,Li L,Wang R,Kovar P,Magoc TJ,Raj




Has Abstract


2018-06-01 00:00:00














  • Hybrid anticancer agents: isothiocyanate-progesterone conjugates as chemotherapeutic agents and insights into their cytotoxicities.

    abstract::New hybrid molecules of isothiocyanate and progesterone and their metal complexes were synthesized exhibiting promising anti-proliferative and pro-apoptotic activity against breast and prostate cancer cells. These metal complex compounds exploited an existing cellular transport pathway for delivery of cytotoxic isothi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Adsule S,Banerjee S,Ahmed F,Padhye S,Sarkar FH

    更新日期:2010-02-01 00:00:00

  • Pyrrolo[3,2,1-ij]quinoline derivatives, a 5-HT2c receptor agonist with selectivity over the 5-HT2a receptor: potential therapeutic applications for epilepsy and obesity.

    abstract::A series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized, evaluated for their activity against the 5-HT2c and 5-HT2a, receptors and found to be agonists at 5-HT2c with selectivity over 5-HT2a. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Isaac M,Slassi A,O'Brien A,Edwards L,MacLean N,Bueschkens D,Lee DK,McCallum K,De Lannoy I,Demchyshyn L,Kamboj R

    更新日期:2000-05-01 00:00:00

  • An unprecedented dual antagonist and agonist of human Transglutaminase 2.

    abstract::Transglutaminase 2 (TG2) is a ubiquitously expressed, Ca(2+)-activated extracellular enzyme in mammals that is maintained in a catalytically dormant state by multiple mechanisms. Although its precise physiological role in the extracellular matrix remains unclear, aberrantly up-regulated TG2 activity is a hallmark of s...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yi MC,Palanski BA,Quintero SA,Plugis NM,Khosla C

    更新日期:2015-11-01 00:00:00

  • The first steps. The attack on the carbonyl carbon of pyridoxal cofactor in pyridoxal-dependent enzymes.

    abstract::A study of the reaction between gaseous aldehydes and amines has implicated proton transfer from wall-associated water. Carbinolamine formation and subsequent dehydration to imine with assistance by wall associated hydroxyl bearing species has not previously been specifically suggested to obtain in the multitude of en...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sonnet PE,Mascavage LM,Dalton DR

    更新日期:2008-01-15 00:00:00

  • Isothiazolidinone inhibitors of PTP1B containing imidazoles and imidazolines.

    abstract::The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are inter...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Douty B,Wayland B,Ala PJ,Bower MJ,Pruitt J,Bostrom L,Wei M,Klabe R,Gonneville L,Wynn R,Burn TC,Liu PC,Combs AP,Yue EW

    更新日期:2008-01-01 00:00:00

  • Substituted benzylamino-6-(trifluoromethyl)pyrimidin-4(1H)-ones: a novel class of selective human A-FABP inhibitors.

    abstract::The synthesis and biological evaluation of novel human A-FABP inhibitors based on the 6-(trifluoromethyl)pyrimidine-4(1H)-one scaffold is described. Two series of compounds, bearing either an amino or carbon substituent in the 2-position of the pyrimidine ring were investigated. Modification of substituents and chain ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ringom R,Axen E,Uppenberg J,Lundbäck T,Rondahl L,Barf T

    更新日期:2004-09-06 00:00:00

  • The binding of cocaine to cyclodextrins.

    abstract::Cocaine binds into beta-cyclodextrin, but not detectably into alpha- or gamma-cyclodextrin, in water solution. NMR studies indicate the geometry of the complex, which is confirmed by molecular mechanics calculations and binding studies on cocaine analogues and cyclodextrin dimers. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nesna N,Lou J,Breslow R

    更新日期:2000-09-04 00:00:00

  • New diterpene furanoids from the Antarctic lichen Huea sp.

    abstract::In the course of ongoing research on protein tyrosine phosphatase 1B (PTP1B) inhibitory compounds from Antarctic lichens, four new diterpene furanoids, hueafuranoids A-D (1-4) have been isolated from the MeOH extract of Antarctic lichen Huea sp. by various chromatographic methods. The structures of these compounds wer...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Cui Y,Yim JH,Lee DS,Kim YC,Oh H

    更新日期:2012-12-15 00:00:00

  • Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitors.

    abstract::The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochemical properties. The series was extended to produce compounds with potent binding affinities and...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Canales E,Carlson JS,Appleby T,Fenaux M,Lee J,Tian Y,Tirunagari N,Wong M,Watkins WJ

    更新日期:2012-07-01 00:00:00

  • Virtual screening and biochemical evaluation to identify new inhibitors of mammalian target of rapamycin (mTOR).

    abstract::Mammalian target of rapamycin (mTOR) is a promising target for the development of anticancer medicines. Here, we report the first example for a successful application of the structure-based virtual screening to identify new mTOR inhibitors. Using the scoring function improved by implementing the ligand solvation effec...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Park H,Choe H,Hong S

    更新日期:2014-02-01 00:00:00

  • Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein.

    abstract::A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Eagon S,Hammill JT,Bach J,Everson N,Sisley TA,Walls MJ,Durham S,Pillai DR,Falade MO,Rice AL,Kimball JJ,Lazaro H,DiBernardo C,Kiplin Guy R

    更新日期:2020-11-01 00:00:00

  • N,N'-bis[4-(N-alkylamidino)phenyl]homopiperazines as anti-Pneumocystis carinii agents.

    abstract::The synthesis, anti-Pneumocystis carinii activity and DNA binding properties of eight new N,N'-bis[4-(N-alkylamidino)phenyl]homopiperazines are reported. Compounds 2 and 8 were the most potent and caused about 70% inhibition of Pneumocystis carinii growth in a cell culture model at 1 microM concentrations. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Huang TL,Tao B,Quarshie Y,Queener SF,Donkor IO

    更新日期:2001-10-22 00:00:00

  • Synthesis and SAR of 1,4,5,6-tetrahydropyridazines as potent cannabinoid CB1 receptor antagonists.

    abstract::The synthesis and structure-activity relationship studies of 1,4,5,6-tetrahydropyridazines are described. The target compounds 3-5 represent a novel class of potent and selective CB1 receptor antagonists. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lange JH,den Hartog AP,van der Neut MA,van Vliet BJ,Kruse CG

    更新日期:2009-10-01 00:00:00

  • An endogenous sleep-inducing compound is a novel competitive inhibitor of fatty acid amide hydrolase.

    abstract::2-Octyl gamma-bromoacetoacetate (O gamma Br), an endogenous compound originally isolated from human cerebrospinal fluid (CSF), has previously been demonstrated to increase REM sleep duration in cats. Based on the chemical structure of O gamma Br and its reported sleep-inducing effects, we synthesized O gamma Br along ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Patricelli MP,Patterson JE,Boger DL,Cravatt BF

    更新日期:1998-03-17 00:00:00

  • Discovery of phenyl acetamides as potent and selective GPR119 agonists.

    abstract::The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zhu C,Wang L,Zhu Y,Guo ZZ,Liu P,Hu Z,Szewczyk JW,Kang L,Chicchi G,Ehrhardt A,Woods A,Seo T,Woods M,van Heek M,Dingley KH,Pang J,Salituro GM,Powell J,Terebetski JL,Hornak V,Campeau LC,Orr RK,Ujjainwalla F,Mil

    更新日期:2017-03-01 00:00:00

  • Characterizing hydration sites in protein-ligand complexes towards the design of novel ligands.

    abstract::Water is an essential part of protein binding sites and mediates interactions to ligands. Its displacement by ligand parts affects the free binding energy of resulting protein-ligand complexes. Therefore the characterization of solvation properties is important for design. Of particular interest is the propensity of l...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章,评审


    authors: Matter H,Güssregen S

    更新日期:2018-08-01 00:00:00

  • Phenylglycine and phenylalanine derivatives as potent and selective HDAC1 inhibitors (SHI-1).

    abstract::An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wilson KJ,Witter DJ,Grimm JB,Siliphaivanh P,Otte KM,Kral AM,Fleming JC,Harsch A,Hamill JE,Cruz JC,Chenard M,Szewczak AA,Middleton RE,Hughes BL,Dahlberg WK,Secrist JP,Miller TA

    更新日期:2008-03-15 00:00:00

  • Synthesis and evaluation of piperazine and homopiperazine analogues of JS-K, an anti-cancer lead compound.

    abstract::Here we report a number of novel JS-K structural analogues with sub-micromolar anti-proliferative activities against human leukemia cell lines HL-60 and U937; JS-K is the anti-cancer lead compound O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate. The ability of these compounds to g...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nandurdikar RS,Maciag AE,Citro ML,Shami PJ,Keefer LK,Saavedra JE,Chakrapani H

    更新日期:2009-05-15 00:00:00

  • SAR studies of novel 5-substituted 2-arylindoles as nonpeptidyl GnRH receptor antagonists.

    abstract::The discovery of the potency-enhancing effect of 5-substitutions on the novel 2-arylindoles as nonpeptidyl GnRH receptor antagonists led to the identification of several analogues with high affinities on the GnRH receptor. The syntheses and SARs of these 5-substituted-2-arylindole analogues are reported. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chu L,Lo JL,Yang YT,Cheng K,Smith RG,Fisher MH,Wyvratt MJ,Goulet MT

    更新日期:2001-02-26 00:00:00

  • QSAR study on pK(a) vis-à-vis physiological activity of sulfonamides: a dominating role of surface tension (inverse steric parameter).

    abstract::The paper describes the dominating role of surface tension (ST) on the modeling, monitoring, and estimating pK(a) for a large series of 43 substituted sulfonamides. Because of the direct correlation of ST with parachor (Pc) vis-a-vis molecular volume (MV), ST is considered as a steric parameter. Single as well as mult...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Thakur M,Thakur A,Khadikar PV,Supuran CT

    更新日期:2005-01-03 00:00:00

  • Multidrug resistance-reversal effects of resin glycosides from Dichondra repens.

    abstract::Investigation of hydrophobic extract of Dichondra repens (Convolvulaceae) led to the isolation of three new resin glycosides dichondrins A-C (1-3), and three known resin glycosides cus-1, cus-2, and cuse 3. All the isolated resin glycosides with an acyclic core were evaluated for their multidrug resistance reversal ac...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Song WB,Wang WQ,Zhang SW,Xuan LJ

    更新日期:2015-02-15 00:00:00

  • Synthesis of Vorinostat and cholesterol conjugate to enhance the cancer cell uptake selectivity.

    abstract::Histone deacetylase (HDAC) inhibitors modulate various cellular functions including proliferation, differentiation, and apoptosis. Vorinostat (SuberAniloHydroxamic Acid, SAHA) is the first HDAC inhibitor approved by FDA for cancer treatment. However, SAHA distributes in cancer tissue and normal tissue in similar level...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Idippily ND,Gan C,Orefice P,Peterson J,Su B

    更新日期:2017-02-15 00:00:00

  • Microwave-assisted synthesis and in vitro antibacterial activity of novel steroidal thiosemicarbazone derivatives.

    abstract::Herein, we reported the synthesis of 16 novel steroidal thiosemicarbazone derivatives via the condensation of steroidal ketones and substituted thiosemicarbazides under solvent-free conditions using microwave irradiation. The yields obtained are in the range of 84-96% using microwave method and 46-62% using convention...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zhao Z,Shi Z,Liu M,Liu X

    更新日期:2012-12-15 00:00:00

  • Inhibition of neutral lipid synthesis by avarols from a marine sponge.

    abstract::The effects of 14 sesquiterpene hydroquinones, including 8 marine sponge-derived avarols (1-8) and 6 semisynthetic derivatives (9-14), on lipid droplet accumulation and neutral lipid synthesis in Chinese hamster ovary (CHO) K1 cells were investigated. In intact CHO-K1 cell assays, avarol (1) markedly decreased the num...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ohshiro T,Kobayashi K,Suzuki A,Yamazaki H,Uchida R,Namikoshi M,Tomoda H

    更新日期:2019-08-15 00:00:00

  • The discovery of potent, selective, and orally bioavailable PDE9 inhibitors as potential hypoglycemic agents.

    abstract::Starting from a non-selective pyrazolo-pyrimidone lead, the sequential use of parallel medicinal chemistry and directed synthesis led to the discovery of potent, highly selective, and orally bioavailable PDE9 inhibitors. The availability of these tools allowed for a thorough evaluation of the therapeutic potential of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Deninno MP,Andrews M,Bell AS,Chen Y,Eller-Zarbo C,Eshelby N,Etienne JB,Moore DE,Palmer MJ,Visser MS,Yu LJ,Zavadoski WJ,Michael Gibbs E

    更新日期:2009-05-01 00:00:00

  • 2('),3(')-didehydro-2('),3(')-dideoxynucleosides are degraded to furfuryl alcohol under acidic conditions.

    abstract::2('),3(')-Didehydro-2('),3(')-dideoxynucleosides are clinically relevant antiviral agents. These nucleosides could be degraded under acidic conditions. Acidic stability studies showed the D4N had the following increasing stability order: D4G

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Shi J,Ray AS,Mathew JS,Anderson KS,Chu CK,Schinazi RF

    更新日期:2004-05-03 00:00:00

  • A new lateral root growth inhibitor from the sponge-derived fungus Aspergillus sp. LS45.

    abstract::Two new γ-lactones, aspergilactones A (1) and B (2), were discovered along with two known compounds, annularin A (3) and pericoterpenoid A (4), from a culture of the sponge-associated fungus Aspergillus sp. LS45. The planar structures of 1-4 were characterized using comprehensive spectroscopic methods and comparison w...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Huang L,Ding L,Li X,Wang N,Yan Y,Yang M,Cui W,Benjamin Naman C,Cheng K,Zhang W,Zhang B,Jin H,He S

    更新日期:2019-07-01 00:00:00

  • Naphthoquinone analogs as inactivators of cdc25 phosphatase.

    abstract::cdc25A and cdc25B were significantly overexpressed in certain types of cancers, and they represent potential therapeutic targets for anticancer drug. In this study, naphthoquinone analogs as cdc25A phosphatase inactivators were investigated. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ham SW,Park J,Lee SJ,Kim W,Kang K,Choi KH

    更新日期:1998-09-22 00:00:00

  • Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3.

    abstract::In an effort to identify new protein kinase inhibitors with increased potency and selectivity, we have developed the microwave-assisted synthesis of thiazolo[5,4-f]quinazolin-9-ones. The effects of eighteen derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3 were investigated. Several turned out to inhibit GSK-3 in the ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Testard A,Logé C,Léger B,Robert JM,Lozach O,Blairvacq M,Meijer L,Thiéry V,Besson T

    更新日期:2006-07-01 00:00:00

  • Synthesis, biological evaluation, and molecular docking studies of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives as anticancer agents.

    abstract::A series of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives have been designed, synthesized and evaluated for their potential antiproliferation activity and Aurora-A kinase inhibitory activity. Among all the compounds, compound 10e possessed the most potent biological activity against HCT116 and MCF-7 cell lines...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li X,Lu X,Xing M,Yang XH,Zhao TT,Gong HB,Zhu HL

    更新日期:2012-06-01 00:00:00