Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs.


:The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.


Bioorg Med Chem Lett


Young RJ,Adams C,Blows M,Brown D,Burns-Kurtis CL,Chan C,Chaudry L,Convery MA,Davies DE,Exall AM,Foster G,Harling JD,Hortense E,Irvine S,Irving WR,Jackson S,Kleanthous S,Pateman AJ,Patikis AN,Roethka TJ,Senger S,




Has Abstract


2011-03-15 00:00:00














  • Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity.

    abstract::Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ashraf-Uz-Zaman M,Sajib MS,Cucullo L,Mikelis CM,German NA

    更新日期:2018-12-15 00:00:00

  • 4-aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators.

    abstract::Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent ac...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xiong H,Brugel TA,Balestra M,Brown DG,Brush KA,Hightower C,Hinkley L,Hoesch V,Kang J,Koether GM,McCauley JP Jr,McLaren FM,Panko LM,Simpson TR,Smith RW,Woods JM,Brockel B,Chhajlani V,Gadient RA,Spear N,Sygowski LA

    更新日期:2010-12-15 00:00:00

  • Estrogenic activity of B-fluorinated o-carborane-1,2-bisphenol synthesized via S(N)Ar reaction.

    abstract::We previously identified o-carborane bisphenol BE360 (4) as a selective estrogen receptor modulator (SERM), which ameliorated bone loss without inducing estrogenic action in uterus of OVX and ORX mice. Here, we synthesized a fluorinated derivative, B-fluorinated o-carborane bisphenol BE310 (5) by means of S(N)Ar react...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ohta K,Ogawa T,Endo Y

    更新日期:2012-07-15 00:00:00

  • Chiral synthesis and pharmacological evaluation of NPS 1407: a potent, stereoselective NMDA receptor antagonist.

    abstract::The stereoselective synthesis and biological activity of NPS 1407 (4a), (S)-(-)-3-amino-1,1-bis(3-fluorophenyl)butane, a potent, stereoselective antagonist of the NMDA receptor, are described. The racemate (4) was found to be active at the NMDA receptor in an in vitro assay, prompting the synthesis of the individual s...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Moe ST,Smith DL,DelMar EG,Shimizu SM,Van Wagenen BC,Balandrin MF,Chien YE,Raszkiewicz JL,Artman LD,White HS,Mueller AL

    更新日期:2000-11-06 00:00:00

  • Cytotoxicity and inhibition of DNA topoisomerase I of polyhydroxylated triterpenoids and triterpenoid glycosides.

    abstract::Cytotoxicity and inhibition on human DNA topoisomerase I (TOP1) and II (TOP2) of 74 plant-originated triterpenoids and triterpenoid glycosides were investigated. The cytotoxic compounds are primarily polyhydroxylated oleananes (GI(50) of A549: 1.0-10.19 microM). Sixteen cytotoxic aesculiosides isolated from Aesculus p...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang P,Ownby S,Zhang Z,Yuan W,Li S

    更新日期:2010-05-01 00:00:00

  • Potent and selective alpha1A adrenoceptor partial agonists--novel imidazole frameworks.

    abstract::Novel imidazole frameworks have been identified as potent partial agonists of the alpha(1A) adrenergic receptor, with good selectivity over the alpha(1B), alpha(1D) and alpha(2A) receptor sub-types. Nitrile 28 possessed attractive CNS drug-like properties with good membrane permeability and no P-pg mediated efflux. 28...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Whitlock GA,Brennan PE,Roberts LR,Stobie A

    更新日期:2009-06-01 00:00:00

  • New triple-helix DNA stabilizing agents.

    abstract::Several substituted quinolin-4-amines and heteroaromatic analogs were synthesized and evaluated for interaction with triplex polydA.2polydT and duplex polydA.polydT by using UV-thermal melting experiments. Excellent triple-helix DNA ligands with high affinity toward T.A.T triplets and triple/duplex selectivity were de...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Strekowski L,Hojjat M,Wolinska E,Parker AN,Paliakov E,Gorecki T,Tanious FA,Wilson WD

    更新日期:2005-02-15 00:00:00

  • [11C]GSK2126458 and [18F]GSK2126458, the first radiosynthesis of new potential PET agents for imaging of PI3K and mTOR in cancers.

    abstract::GSK2126458 is a highly potent inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with low picomolar to subnanomolar activity. [(11)C]GSK2126458 and [(18)F]GSK2126458, new potential PET agents for imaging of PI3K and mTOR in cancer, were first designed and synthesized in 40-50% and 2...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang M,Gao M,Miller KD,Sledge GW,Zheng QH

    更新日期:2012-02-15 00:00:00

  • Nonbenzamidine acylsulfonamide tissue factor-factor VIIa inhibitors.

    abstract::Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions we...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Glunz PW,Zhang X,Zou Y,Delucca I,Nirschl AH,Cheng X,Weigelt CA,Cheney DL,Wei A,Anumula R,Luettgen JM,Rendina AR,Harpel M,Luo G,Knabb R,Wong PC,Wexler RR,Priestley ES

    更新日期:2013-09-15 00:00:00

  • Antifungal trichothecene sesquiterpenes obtained from the culture broth of marine-derived Trichoderma cf. brevicompactum and their structure-activity relationship.

    abstract::Two new trichothecene sesquiterpenes, trichobreols D (1) and E (2), were isolated from the culture broth of marine-derived Trichoderma cf. brevicompactum together with trichobreol A (3). The structures of 1 and 2 were assigned on the basis of their spectroscopic data. Compound 1 inhibited the growth of two yeast-like ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yamazaki H,Yagi A,Takahashi O,Yamaguchi Y,Saito A,Namikoshi M,Uchida R

    更新日期:2020-09-01 00:00:00

  • Synthesis and cytotoxicity of (-)-renieramycin G analogs.

    abstract::(-)-Renieramycin G and fifteen C-22 analogs were prepared employing l-tyrosine as the chiral starting material. These analogs, along with (-)-renieramycin G itself, were evaluated in vitro for cytotoxicity against HCT-8, BEL-7402, A2780, MCF-7, A549, BGC-823, Ketr3, KB, Hela cells. The IC(50) values of most of these a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu W,Dong W,Liao X,Yan Z,Guan B,Wang N,Liu Z

    更新日期:2011-03-01 00:00:00

  • Pharmacophore modeling and in silico screening for new KDR kinase inhibitors.

    abstract::In order to elucidate the essential structural features for KDR kinase inhibitors, three-dimensional pharmacophore hypotheses were built on the basis of a set of known KDR kinase inhibitors selected from the literature with CATALYST program. Several methods tools used in validation of pharmacophore hypothsis were pres...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yu H,Wang Z,Zhang L,Zhang J,Huang Q

    更新日期:2007-04-15 00:00:00

  • Synthesis and biological evaluation of 2-arylimino-3-pyridin-thiazolineone derivatives as antibacterial agents.

    abstract::With an intention to find more potent antibacterial agents, four halogen disubstituted thiazolineone derivatives (2a-d), five halogen monosubstituted thiazolineone derivatives (2e-i), and eleven 2-arylimino-3-pyridin-thiazolineone derivatives (2j-t) were synthesized and screened for their antibacterial activity, bacte...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Cai MG,Wu Y,Chang J

    更新日期:2016-05-15 00:00:00

  • Novel endoperoxides: synthesis and activity against Candida species.

    abstract::Fifteen new endoperoxides have been synthesised and tested for activity against pathogenic Candida species. These endoperoxides can be prepared in high yields, in one to three steps, from inexpensive starting materials. Despite chemical and structural similarities, their inhibitory activity against Candida growth vari...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Macreadie P,Avery T,Greatrex B,Taylor D,Macreadie I

    更新日期:2006-02-15 00:00:00

  • Inhibition of the strand transfer step of HIV-1 integrase by non-natural dinucleotides.

    abstract::New, non-natural dinucleotide 5'-monophosphates, with a surrogate isonucleoside component of l-related stereochemistry at the 'terminal' position, have been synthesized. Structures of 2a-c were confirmed by multinuclear NMR spectra ((1)H, (13)C, (31)P, COSY), UV hypochromicity and FAB HRMS data. These compounds are to...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chi G,Neamati N,Nair V

    更新日期:2004-10-04 00:00:00

  • Dimeric unnatural polyproline-rich peptides with enhanced antibacterial activity.

    abstract::We report a dimerization strategy to enhance the antibacterial potency of an otherwise weak cationic amphiphilic polyproline helical (CAPH) peptide. Overall, the dimeric CAPHs were more active against Escherichia coli and Staphylococcus aureus than the monomeric counterpart, reaching up to a 60-fold increase in potenc...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hernandez-Gordillo V,Geisler I,Chmielewski J

    更新日期:2014-01-15 00:00:00

  • Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.

    abstract::The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar subs...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ng RA,Sun M,Bowers S,Hom RK,Probst GD,John V,Fang LY,Maillard M,Gailunas A,Brogley L,Neitz RJ,Tung JS,Pleiss MA,Konradi AW,Sham HL,Dappen MS,Adler M,Yao N,Zmolek W,Nakamura D,Quinn KP,Sauer JM,Bova MP,Ruslim

    更新日期:2013-08-15 00:00:00

  • Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent sphingosine-1-phosphate receptor subtype-1 agonists.

    abstract::In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Evindar G,Bernier SG,Kavarana MJ,Doyle E,Lorusso J,Kelley MS,Halley K,Hutchings A,Wright AD,Saha AK,Hannig G,Morgan BA,Westlin WF

    更新日期:2009-01-15 00:00:00

  • Discovery of peptidic miR-21 processing inhibitor by mirror image phage display: A novel method to generate RNA binding D-peptides.

    abstract::A novel method to generate RNA binding D-peptide has been developed. To achieve the screening method, phage display was applied to "Mirrored" RNA (L-enantiomer of RNA). We have selected pre-miR21 as an initial screening target to demonstrate the method. The mirrored pre-miR-21 binding peptide sequences were successful...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sakamoto K,Otake K,Umemoto T

    更新日期:2017-02-15 00:00:00

  • Syntheses and structure-activity relationship (SAR) studies of 2,5-diazabicyclo[2.2.1]heptanes as novel alpha7 neuronal nicotinic receptor (NNR) ligands.

    abstract::Biaryl substituted 2,5-diazabicyclo[2.2.1]heptanes have been synthesized and tested for their affinity toward alpha7 neuronal nicotinic receptors (NNRs). SAR studies established that 5-N-methyl substituent, heteroaryl linker and the nature of terminal aryl group are critical for the ligand to achieve potent alpha7 NNR...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li T,Bunnelle WH,Ryther KB,Anderson DJ,Malysz J,Helfrich R,Grønlien JH,Håkerud M,Peters D,Schrimpf MR,Gopalakrishnan M,Ji J

    更新日期:2010-06-15 00:00:00

  • Conformational study of a highly specific CXCR4 inhibitor, T140, disclosing the close proximity of its intrinsic pharmacophores associated with strong anti-HIV activity.

    abstract::We report the solution structure of T140, a truncated polyphemusin peptide analogue that efficiently inhibits infection of target cells by T-cell line-tropic strains of HIV-1 through its specific binding to a chemokine receptor, CXCR4. Nuclear magnetic resonance analysis and molecular dynamic calculations revealed tha...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tamamura H,Sugioka M,Odagaki Y,Omagari A,Kan Y,Oishi S,Nakashima H,Yamamoto N,Peiper SC,Hamanaka N,Otaka A,Fujii N

    更新日期:2001-02-12 00:00:00

  • Potassium channel blocking 1,2-bis(aryl)ethane-1,2-diamines active as antiarrhythmic agents.

    abstract::Atrial fibrillation (AF) is a major cause of stroke, heart failure, sudden death and cardiovascular morbidity. The Kv1.5 potassium channel conducts the IKur current and has been demonstrated to be predominantly expressed in atrial versus ventricular tissue. Blockade of Kv1.5 has been proven to be an effective approach...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kajanus J,Antonsson T,Carlsson L,Jurva U,Pettersen A,Sundell J,Inghardt T

    更新日期:2019-05-15 00:00:00

  • Identification of 2,3,6-trisubstituted quinoxaline derivatives as a Wnt2/β-catenin pathway inhibitor in non-small-cell lung cancer cell lines.

    abstract::We screened 1434 small heterocyclic molecules and identified thirteen 2,3,6-trisubstituted quinoxaline derivatives that were able to inhibit the Wnt/β-catenin signal pathway and cell proliferation. In the screen, some of the hit compounds such as the ethylene group-coupled quinoxaline derivatives were shown to hold pr...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lee SB,Park YI,Dong MS,Gong YD

    更新日期:2010-10-01 00:00:00

  • Antibacterial activity of substituted 5-methylbenzo[c]phenanthridinium derivatives.

    abstract::Antibiotic resistance has prompted efforts to discover antibiotics with novel mechanisms of action. FtsZ is an essential protein for bacterial cell division, and has been viewed as an attractive target for the development of new antibiotics. Sanguinarine is a benzophenanthridine alkaloid that prevents cytokinesis in b...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Parhi A,Kelley C,Kaul M,Pilch DS,LaVoie EJ

    更新日期:2012-12-01 00:00:00

  • Synthesis and preliminary cytotoxicity of nitrogen mustard derivatives of distamycin A.

    abstract::Distamycin and nitrogen mustard conjugates, in which the nitrogen mustard unit was coupled to the C-terminus of the pyrrole, were synthesized. The switching of the nitrogen mustard unit from the N-terminus to the C-terminus did not compromise the compound's cytotoxicity. Compound 3, bearing three pyrrole units, was hi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang Y,Wright SC,Larrick JW

    更新日期:2003-02-10 00:00:00

  • Aminopyrazine CB1 receptor inverse agonists.

    abstract::A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse ago...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wustrow DJ,Maynard GD,Yuan J,Zhao H,Mao J,Guo Q,Kershaw M,Hammer J,Brodbeck RM,Near KE,Zhou D,Beers DS,Chenard BL,Krause JE,Hutchison AJ

    更新日期:2008-06-01 00:00:00

  • Effects of alkyl parabens on plant pathogenic fungi.

    abstract::Alkyl parabens are used as antimicrobial preservatives in cosmetics, food, and pharmaceutical products. However, the mode of action of these chemicals has not been assessed thoroughly. In this study, we determined the effects of alkyl parabens on plant pathogenic fungi. All the fungi tested, were susceptible to parabe...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ito S,Yazawa S,Nakagawa Y,Sasaki Y,Yajima S

    更新日期:2015-04-15 00:00:00

  • Design and synthesis of C10 modified and ring-truncated canthin-6-one analogues as effective membrane-active antibacterial agents.

    abstract::A series of canthin-6-one analogues were designed and synthesized in order to study their antibacterial activity and structure-activity relationships. Compound 22 showed a broad spectrum of antibacterial activity and exhibited better bactericidal effect (8-fold superiority against Staphylococcus aureus and 2-fold supe...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Dai J,Dan W,Zhang Y,He M,Wang J

    更新日期:2018-10-01 00:00:00

  • P3-P4 ureas and reverse carbamates as potent HCV NS3 protease inhibitors: Effective transposition of the P4 hydrogen bond donor.

    abstract::A series of tripeptidic acylsulfonamide inhibitors of HCV NS3 protease were prepared that explored structure-activity relationships (SARs) at the P4 position, and their in vitro and in vivo properties were evaluated. Enhanced potency was observed in a series of P4 ureas; however, the PK profiles of these analogues wer...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Venables BL,Sin N,Wang AX,Sun LQ,Tu Y,Hernandez D,Sheaffer A,Lee M,Dunaj C,Zhai G,Barry D,Friborg J,Yu F,Knipe J,Sandquist J,Falk P,Parker D,Good AC,Rajamani R,McPhee F,Meanwell NA,Scola PM

    更新日期:2018-06-01 00:00:00

  • Structure-activity relationships of novel anti-malarial agents. Part 6: N-(4-arylpropionylamino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides.

    abstract::We have demonstrated that the p-trifluoromethylphenylpropionylamino residue at the 2-position of the core structure leads to an active benzophenone-type anti-malarial agent. The attempt to improve water solubility by introduction of an amino group into the alpha-position of the arylpropionyl residue resulted in decrea...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wiesner J,Fucik K,Kettler K,Sakowski J,Ortmann R,Jomaa H,Schlitzer M

    更新日期:2003-05-05 00:00:00