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














  • Syntheses and biological evaluation of ring-C modified colchicine analogs.

    abstract::Ring-C modified alkaloids were synthesized from colchicine using iminonitroso Diels-Alder reactions in a highly regio- and stereoselective fashion. Several analogs exhibited cytotoxic activity similar to that of colchicine itself against PC-3 and MCF-7 cancer cell lines, by serving as prodrugs of colchicine through re...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yang B,Zhu ZC,Goodson HV,Miller MJ

    更新日期:2010-06-15 00:00:00

  • Antitumor activity of tetrahydroisoquinoline analogues 3-epi-jorumycin and 3-epi-renieramycin G.

    abstract::Analogues of the tetrahydroisoquinoline family of antitumor antibiotics, 3-epi-jorumycin (3) and 3-epi-renieramycin G (4), in addition to their respective parent natural products (-)-jorumycin (1) and (-)-renieramycin G (2) were evaluated against both human colon (HCT-116) and human lung (A549) cancer cell lines. (-)-...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lane JW,Estevez A,Mortara K,Callan O,Spencer JR,Williams RM

    更新日期:2006-06-15 00:00:00

  • Pharmacokinetics and metabolism studies on (3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy) pyrazolo[1,5-d][1,2,4]triazine, a functionally selective GABA(A) alpha5 inverse agonist for cognitive dysfunction.

    abstract::(3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (1) was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5 receptors and enhances performance in animal models of cognition. The routes of metabolis...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Jones P,Atack JR,Braun MP,Cato BP,Chambers MS,O'Connor D,Cook SM,Hobbs SC,Maxey R,Szekeres HJ,Szeto N,Wafford KA,MacLeod AM

    更新日期:2006-02-15 00:00:00

  • The solid phase synthesis of a series of tri-substituted hydantoin ligands for the somatostatin SST5 receptor.

    abstract::A series of trisubstituted hydantoins has been prepared by a versatile solid phase route employing primary alcohols, amines and amino acids as the monomeric building blocks. Several compounds showed submicromolar affinity in binding assays at recombinant human somatostatin receptors. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sciciński JJ,Barker MD,Murray PJ,Jarvie EM

    更新日期:1998-12-15 00:00:00

  • Towards new antibiotics targeting bacterial transglycosylase: Synthesis of a Lipid II analog as stable transition-state mimic inhibitor.

    abstract::Described here is the asymmetric synthesis of iminosugar 2b, a Lipid II analog, designed to mimic the transition state of transglycosylation catalyzed by the bacterial transglycosylase. The high density of functional groups, together with a rich stereochemistry, represents an extraordinary challenge for chemical synth...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang X,Krasnova L,Wu KB,Wu WS,Cheng TJ,Wong CH

    更新日期:2018-09-01 00:00:00

  • Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).

    abstract::Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cel...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: MacKinnon CH,Lau K,Burch JD,Chen Y,Dines J,Ding X,Eigenbrot C,Heifetz A,Jaochico A,Johnson A,Kraemer J,Kruger S,Krülle TM,Liimatta M,Ly J,Maghames R,Montalbetti CA,Ortwine DF,Pérez-Fuertes Y,Shia S,Stein DB,Tran

    更新日期:2013-12-01 00:00:00

  • Design, synthesis and antimalarial activity of benzene and isoquinoline sulfonamide derivatives.

    abstract::A new series of benzene and isoquinoline sulfonamide derivatives were synthesized by nucleophilic displacement reaction on benzene and isoquinoline sulfonyl chlorides by substituted amines (primary and secondary). The title compounds were evaluated for antimalarial activity against Plasmodium falciparum in vitro and s...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kumar Parai M,Panda G,Srivastava K,Kumar Puri S

    更新日期:2008-01-15 00:00:00

  • Effect of incorporating a thiophene tail in the scaffold of acetazolamide on the inhibition of human carbonic anhydrase isoforms I, II, IX and XII.

    abstract::The high resolution crystal structure of 5-(2-thienylacetamido)-1,3,4-thiadiazole-2-sulfonamide complexed to human (h) carbonic anhydrase (CA, EC isoform hCA II is reported. The compound binds in a similar manner with acetazolamide when the sulfamoyl-thiadiazolyl-acetamido fragment of the two compounds is con...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Biswas S,McKenna R,Supuran CT

    更新日期:2013-10-15 00:00:00

  • Discovery of novel imidazo[1,2-a]pyridines as inhibitors of the insulin-like growth factor-1 receptor tyrosine kinase.

    abstract::We disclose a novel series of insulin-like growth factor-1 receptor kinase inhibitors based on the 3-(pyrimidin-4-yl)-imidazo[1,2-a]pyridine scaffold. The influence on the inhibitory activity of substitution on the imidazopyridine and at the C5 position of the pyrimidine is discussed. In the course of this optimizatio...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ducray R,Simpson I,Jung FH,Nissink JW,Kenny PW,Fitzek M,Walker GE,Ward LT,Hudson K

    更新日期:2011-08-15 00:00:00

  • Identification of prostaglandin D2 receptor antagonists based on a tetrahydropyridoindole scaffold.

    abstract::A new series of indole-based antagonists of the PGD(2) receptor subtype 1 (DP1 receptor) was identified and the progress of the structure-activity relationship study to the identification of potent and selective antagonists is presented. Selective DP1 antagonists with high potency and selectivity were prepared. Of par...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Beaulieu C,Guay D,Wang Z,Leblanc Y,Roy P,Dufresne C,Zamboni R,Berthelette C,Day S,Tsou N,Denis D,Greig G,Mathieu MC,O'Neill G

    更新日期:2008-04-15 00:00:00


    abstract::N6-Substituted adenosine analogues containing cyclic hydrazines or chiral hydroxy (ar)alkyl groups, designed to interact with the S2 and S3 receptor subregions, have been synthesized and their binding to the adenosine A1 and A2A receptors have been investigated. Examples of both types of compounds were found to exhibi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ha SB,Melman N,Jacobson KA,Nair V

    更新日期:1997-12-16 00:00:00

  • Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives.

    abstract::The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of th...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kusumi K,Shinozaki K,Yamaura Y,Hashimoto A,Kurata H,Naganawa A,Otsuki K,Matsushita T,Sekiguchi T,Kakuuchi A,Yamamoto H,Seko T

    更新日期:2016-02-15 00:00:00

  • Leptostatin: a synthetic hybrid of the cytotoxic polyketides callystatin A and leptomycin B.

    abstract::Four stereoisomeric hybrids of the polyketide natural products callystatin A and leptomycin B have been prepared by parallel synthetic routes involving chiral allenylstannane methodology. Like their natural counterparts, these hybrids exhibit nanomolar levels of cytotoxicity toward HCT-116 human colon cancer cells. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Marshall JA,Mikowski AM,Bourbeau MP,Schaaf GM,Valeriote F

    更新日期:2006-01-15 00:00:00

  • Identification and SAR around N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide, a selective alpha2C adrenergic receptor antagonist.

    abstract::The discovery of the CNS-penetrant and selective alpha(2C) adrenergic receptor antagonist N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide, 13 is described. Structure-activity studies demonstrate the structural requirements for binding affinity, functional activity, a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Patel SD,Habeski WM,Min H,Zhang J,Roof R,Snyder B,Bora G,Campbell B,Li C,Hidayetoglu D,Johnson DS,Chaudhry A,Charlton ME,Kablaoui NM

    更新日期:2008-10-15 00:00:00

  • Eicosapentaenoic-acid-derived isoprostanes: synthesis and discovery of two major isoprostanes.

    abstract::The stereospecific synthesis of two all-syn-EPA-derived isoprostanes (iPs), 5-epi-8,12-iso-iPF(3alpha)-VI 17 and 8,12-iso-iPF(3alpha)-VI 18, has been accomplished. These two synthetic probes have been used to discover and identify their presence in human urine. The eventual quantitative measurement of these two iPs ma...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chang CT,Patel P,Kang N,Lawson JA,Song WL,Powell WS,FitzGerald GA,Rokach J

    更新日期:2008-10-15 00:00:00

  • Bioisostere of valtrate, anti-HIV principle by inhibition for nuclear export of Rev.

    abstract::Rational design by the MO calculation disclosed 5,6-dihydrovaltrate (2) as the bioisostere of valtrate (1), the Rev-export inhibitor with anti-HIV activity. The synthesis of 2 was accomplished by ingenious use of asymmetric Diels-Alder reaction and stereoselective epoxidation associated with the adjacent hydroxyl grou...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tamura S,Shimizu N,Fujiwara K,Kaneko M,Kimura T,Murakami N

    更新日期:2010-04-01 00:00:00

  • The development of benzo- and naphtho-fused quinoline-2,4-dicarboxylic acids as vesicular glutamate transporter (VGLUT) inhibitors reveals a possible role for neuroactive steroids.

    abstract::Substituted quinoline-2,4-dicarboxylates (QDCs) are conformationally-restricted mimics of glutamate that were previously reported to selectively block the glutamate vesicular transporters (VGLUTs). We find that expanding the QDC scaffold to benzoquinoline dicarboxylic acids (BQDC) and naphthoquinoline dicarboxylic aci...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Carrigan CN,Patel SA,Cox HD,Bolstad ES,Gerdes JM,Smith WE,Bridges RJ,Thompson CM

    更新日期:2014-02-01 00:00:00

  • Nepsilon-thioacetyl-lysine: a multi-facet functional probe for enzymatic protein lysine Nepsilon-deacetylation.

    abstract::Peptides containing Nepsilon-thioacetyl-lysine and Nepsilon-acetyl-lysine were evaluated for their de(thio)acetylation catalyzed by human HDAC8 and SIRT1, two distinct protein deacetylases. Nepsilon-Thioacetyl-lysine was found to be a mimic of Nepsilon-acetyl-lysine for HDAC8-catalyzed reaction, but to confer inhibiti...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fatkins DG,Monnot AD,Zheng W

    更新日期:2006-07-15 00:00:00

  • Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015-2019).

    abstract::Sustained proliferative capacity and gene dysregulation are hallmarks of cancer. In mammalian cells, cyclin-dependent kinases (CDKs) control critical cell cycle checkpoints and key transcriptional events in response to extracellular and intracellular signals leading to proliferation. Significant clinical activity for ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章,评审


    authors: Sánchez-Martínez C,Lallena MJ,Sanfeliciano SG,de Dios A

    更新日期:2019-10-15 00:00:00

  • Prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides can increase anti-HCV activity and enhance nucleotide triphosphate concentrations in vitro.

    abstract::A number of prodrugs of HCV-active purine nucleoside analogues 2'-C-methyl 4-aza-9-deaza adenosine 1, 2'-C-methyl 4-aza-7,9-dideaza adenosine 2, 2'-C-methyl 4-aza-9-deaza guanosine 3 and 2'-C-methyl 4-aza-7,9-dideaza guanosine 4 were prepared and evaluated to improve potency, selectivity and liver targeting. Phosphora...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tyndall EM,Draffan AG,Frey B,Pool B,Halim R,Jahangiri S,Bond S,Wirth V,Luttick A,Tilmanis D,Thomas J,Porter K,Tucker SP

    更新日期:2015-02-15 00:00:00

  • Synthesis of enamino-2-oxindoles via conjugate addition between α-azido ketones and 3-alkenyl oxindoles: Cytotoxicity evaluation and apoptosis inducing studies.

    abstract::A facile method for the construction of double bond between 3-ylidene oxindoles and α-azido ketones has been successfully accomplished with a mild base. This method features azido reduction with concomitant double bond formation to provide the new class of bioactive enamino-2-oxindoles. These new compounds were screen...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kumar NP,Vanjari Y,Thatikonda S,Pooladanda V,Sharma P,Sridhar B,Godugu C,Kamal A,Shankaraiah N

    更新日期:2018-12-01 00:00:00

  • Total syntheses and stereochemical reassignments of mollenines A and B.

    abstract::Total syntheses of prenylated pyrrolidinoindoline alkaloids, (-)-mollenines A [(-)-1'] and B (2'), were accomplished via three- and four-step sequences including a bioinspired indole prenylation reaction followed by dioxomorpholine ring formation. Then, the stereochemistry of mollenines A and B was reassigned to 3S,6S...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Shiomi S,Wada K,Umeda Y,Kato H,Tsukamoto S,Ishikawa H

    更新日期:2018-09-01 00:00:00

  • Discovery of novel 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives as HIF prolyl 4-hydroxylase inhibitors; SAR, synthesis and modeling evaluation.

    abstract::The design, synthesis, and capacity to inhibit HIF prolyl 4-hydroxylases (PHDs) are described for 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide analogs. These analogs revealed two kinds of novel scaffolds as PHD2 inhibitors. Synthetic routes were developed for the preparation of their analogs containing the ne...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hong YR,Kim HT,Ro S,Cho JM,Lee SH,Kim IS,Jung YH

    更新日期:2014-07-15 00:00:00

  • Solid-phase synthesis of 2,3-disubstituted indoles: discovery of a novel, high-affinity, selective h5-HT2A antagonist.

    abstract::The application of a novel solid-phase synthesis of 2,3-disubstituted indoles utilizing a carbamate indole linker is described resulting in the identification of the novel, high-affinity, selective h5-HT2A antagonist 19. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Smith AL,Stevenson GI,Lewis S,Patel S,Castro JL

    更新日期:2000-12-18 00:00:00

  • Amides of xanthurenic acid as zinc-dependent inhibitors of Lp-PLA(2).

    abstract::AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100nM inhibitor of Lp-PLA(2). However, in the presence of EDTA the inhibitory activity of AX10185 was extinguished while the enzymatic activity of Lp-PLA(2) did not change. Subsequent metal screening experiments determined the inhibition to be Zn(2+)...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lin EC,Hu Y,Amantea CM,Pham LM,Cajica J,Okerberg E,Brown HE,Fraser A,Du L,Kohno Y,Ishiyama J,Kozarich JW,Shreder KR

    更新日期:2012-01-15 00:00:00

  • Use of parallel-synthesis combinatorial libraries for rapid identification of potent FKBP12 inhibitors.

    abstract::Using simple, inexpensive equipment, we have used solution-phase parallel synthesis to rapidly prepare hundreds of sulfonamide- and urea-containing FKBP inhibitors, resulting in rapid identification of extremely potent compounds in these series. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Choi C,Li JH,Vaal M,Thomas C,Limburg D,Wu YQ,Chen Y,Soni R,Scott C,Ross DT,Guo H,Howorth P,Valentine H,Liang S,Spicer D,Fuller M,Steiner J,Hamilton GS

    更新日期:2002-05-20 00:00:00

  • Synthesis of new fluoroquinolones and evaluation of their in vitro activity on Toxoplasma gondii and Plasmodium spp.

    abstract::The synthesis of four new computer-designed fluoroquinolones which have been predicted by QSAR analysis to be active against the protozoa Toxoplasma gondii is described. These compounds are inhibitory in vitro for T. gondii. One of these compounds has a remarkably high activity comparable to that of trovafloxacin. It ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Anquetin G,Rouquayrol M,Mahmoudi N,Santillana-Hayat M,Gozalbes R,Greiner J,Farhati K,Derouin F,Guedj R,Vierling P

    更新日期:2004-06-07 00:00:00

  • Synthesis of 4'-modified noraristeromycins to clarify the effect of the 4'-hydroxyl groups for inhibitory activity against S-adenosyl-L-homocysteine hydrolase.

    abstract::4'-Modified noraristeromycin (NAM) analogs, 4'-sulfo-, 4'-sulfamoy, 4'-azido and 4'-amino-NAM, were systematically synthesized. The inhibitory activities of these analogs and related compounds against Plasmodium falciparum and human S-adenosyl-L-homocysteine hydrolase were investigated. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ando T,Kojima K,Chahota P,Kozaki A,Milind ND,Kitade Y

    更新日期:2008-04-15 00:00:00

  • Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition.

    abstract::An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the pot...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Mihalic JT,Fan P,Chen X,Chen X,Fu Y,Motani A,Liang L,Lindstrom M,Tang L,Chen JL,Jaen J,Dai K,Li L

    更新日期:2012-06-01 00:00:00

  • Research on PEGylation of porcine prothrombin for improving biostability and reducing animal immunogenicity.

    abstract::Prothrombin is a vitamin K-dependent serine protease and plays pivotal roles in both procoagulant and anticoagulant pathway of hemostasis. In this study, prothrombin purified from porcine plasma was modified through PEGylation at N-terminal residue using 40 kDa PEG-phenyl-isothiocyanate (PIT-PEG40K). The monoPEGylated...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zhou JG,Chen YM

    更新日期:2011-06-01 00:00:00