Design, synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists.


:Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.


Bioorg Med Chem Lett


Dounay AB,Barta NS,Campbell BM,Coleman C,Collantes EM,Denny L,Dutta S,Gray DL,Hou D,Iyer R,Maiti SN,Ortwine DF,Probert A,Stratman NC,Subedi R,Whisman T,Xu W,Zoski K




Has Abstract


2010-02-01 00:00:00














  • Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.

    abstract::Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Govek SP,Nagasawa JY,Douglas KL,Lai AG,Kahraman M,Bonnefous C,Aparicio AM,Darimont BD,Grillot KL,Joseph JD,Kaufman JA,Lee KJ,Lu N,Moon MJ,Prudente RY,Sensintaffar J,Rix PJ,Hager JH,Smith ND

    更新日期:2015-11-15 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

  • Synthesis and antitumor activity of leinamycin derivatives: modifications of C-8 hydroxy and C-9 keto groups.

    abstract::A series of leinamycin derivatives were synthesized and evaluated for antitumor activity. Modifications at C-8 and C-9 positions revealed a broad structure-activity relationship in vitro and some derivatives showed potent antiproliferative activity against HeLa S3 cells. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kanda Y,Ashizawa T,Saitoh Y,Saito H,Gomi K,Okabe M

    更新日期:1998-04-21 00:00:00

  • A quantitative assessment of hERG liability as a function of lipophilicity.

    abstract::The impact of lipophilicity as a factor contributing to hERG potency is assessed for a large dataset of compounds of differing ionisation type. This dataset is derived from compounds tested in the IonWorks-based in vitro electrophysiology hERG assay at AstraZeneca. Using logistic regression, a quantification of the ri...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Waring MJ,Johnstone C

    更新日期:2007-03-15 00:00:00

  • Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay.

    abstract::Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Arns S,Tan J,Sun S,Galey A,Zisman N,Ross F,Udechukwu J,Dercho S,Gusti V,Paquette J,Webb M,Bourque E,Withers SG,Liggins R

    更新日期:2015-06-15 00:00:00

  • Synthesis of non-nucleoside anti-viral cyclopropylcarboxacyl hydrazones and initial anti-HSV-1 structure-activity relationship studies.

    abstract::The synthesis of a lead anti-viral cyclopropyl carboxy acyl hydrazone 4F17 (5) and three sequential arrays of structural analogues along with the initial assessment and optimization of the antiviral pharmacophore against the herpes simplex virus type 1 (HSV-1) are reported. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: McNulty J,Babu Dokuburra C,D'Aiuto L,Demers M,McClain L,Piazza P,Williamson K,Zheng W,Nimgaonkar VL

    更新日期:2020-12-15 00:00:00

  • Imidazolopyrazinones as potential antioxidants.

    abstract::A series of imidazolopyrazinones 3, substituted at C-2, and C-2/C-6, has been prepared. The compounds behaved as quenchers of superoxide anion. The more active compounds are structurally related to coelenterazine, a natural substrate of marine bioluminescence. Theoretical parameters based on Hartree-Fock instabilities...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Devillers I,Dive G,De Tollenaere C,Falmagne B,de Wergifosse B,Rees JF,Marchand-Brynaert J

    更新日期:2001-09-03 00:00:00

  • Synthesis and evaluation of potent pyrrolidine H(3) antagonists.

    abstract::The synthesis and biological evaluation of novel antagonists of the rat H(3) receptor are described. These compounds differ from prototypical H(3) antagonists in that they do not contain an imidazole moiety, but rather a substituted aminopyrrolidine moiety. A systematic modification of the substituents on the aminopyr...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Vasudevan A,Conner SE,Gentles RG,Faghih R,Liu H,Dwight W,Ireland L,Kang CH,Esbenshade TA,Bennani YL,Hancock AA

    更新日期:2002-11-04 00:00:00

  • Electrochemical and esr spin trap studies of a new iron tetra-catecholamide complex.

    abstract::A new siderophore, N5,N6-thiodipropanoyl-bis[N1,N10-bis(2,3-dihydroxy benzoyl-spermidine)]-Fe (III) complex or H2LFe has been synthesised. The reaction of the reduced form of this complex with dioxygen has been investigated through electrochemical study and revealed the formation of a new species assumed to be H2O2. T...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Cheraïti N,Brik ME,Keita B,Nadjo L,Gaudemer A

    更新日期:1999-08-16 00:00:00

  • Synthesis and biological evaluation of sulfonamidooxazoles and beta-keto sulfones: selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I.

    abstract::The design, synthesis, and biological evaluation of arylsulfonamidooxazoles as 11beta-HSD1 inhibitors and the serendipitous discovery of beta-keto sulfones as potent 11beta-HSD1 inhibitors are described here. These two classes of compounds are not active against 11beta-HSD2 and therefore may have significant therapeut...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xiang J,Ipek M,Suri V,Massefski W,Pan N,Ge Y,Tam M,Xing Y,Tobin JF,Xu X,Tam S

    更新日期:2005-06-02 00:00:00

  • Synthesis and immunostimulatory activity of sugar-conjugated TLR7 ligands.

    abstract::Toll-like receptors (TLRs) are a type of pattern recognition receptors (PRRs), which are activated by recognizing pathogen-associated molecular patterns (PAMPs). The activation of TLRs initiates innate immune responses and subsequently leads to adaptive immune responses. TLR agonists are effective immuomodulators in v...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Baba A,Wakao M,Shinchi H,Chan M,Hayashi T,Yao S,Cottam HB,Carson DA,Suda Y

    更新日期:2020-02-01 00:00:00

  • Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists.

    abstract::Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd gen...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Du W,Jewell JP,Lin LS,Colandrea VJ,Xiao JC,Lao J,Shen CP,Bateman TJ,Reddy VB,Ha SN,Shah SK,Fong TM,Hale JJ,Hagmann WK

    更新日期:2009-09-01 00:00:00

  • Parallel solid-phase synthesis of a model library of 7alpha-alkylamide estradiol derivatives as potential estrogen receptor antagonists.

    abstract::The C17-THP derivative of 7alpha-(11-azidoundecanyl)-estradiol (4) was synthesized and coupled to an aminomethyl resin via a photolabile o-nitrobenzyl linker. Reduction of the azide by the Staudinger reaction to its corresponding amine followed by acylation using four activated NFmoc protected amino acids gave a first...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tremblay MR,Simard J,Poirier D

    更新日期:1999-10-04 00:00:00

  • Discovery of new peptide-based catalysts for the direct asymmetric aldol reaction.

    abstract::A series of oligo-peptide based catalysts were prepared using Fmoc solid-phase peptide synthesis. It was found that peptides with N-terminal proline residues catalyzed an aldol reaction yielding enantiomeric enriched product. Peptide H-Pro-Glu-Leu-Phe-OH catalyzed the reaction with good activity and moderate enantiose...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kofoed J,Nielsen J,Reymond JL

    更新日期:2003-08-04 00:00:00

  • Synthesis and evaluation of a library of 2,5-bisdiamino-benzoquinone derivatives as probes to modulate protein-protein interactions in prions.

    abstract::A small library combining two different benzoquinone cores with seven (L) amino acid methyl esters (alanine, Nomega-nitro-arginine, Nepsilon-BOC-lysine, isoleucine, methionine, phenylalanine and tryptophan) was prepared and tested for prion replication inhibition in ScGT1 cells. The most potent hit, 6a, displayed an E...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tran HN,Bongarzone S,Carloni P,Legname G,Bolognesi ML

    更新日期:2010-03-15 00:00:00

  • Diaminopyrimidine and diaminopyridine 5-HT7 ligands.

    abstract::The present studies have identified a series of diaminopyrimidines and diaminopyridines as novel 5-HT(7) receptor ligands. Three regiosiomeric classes of pyrimidines and four regioisomeric classes of pyridines were synthesized and analyzed for binding to the 5-HT(7) receptor. The 5-HT(7) binding affinities of differen...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Denhart DJ,Purandare AV,Catt JD,King HD,Gao A,Deskus JA,Poss MA,Stark AD,Torrente JR,Johnson G,Mattson RJ

    更新日期:2004-08-16 00:00:00

  • Clinical status of duplex RNA.

    abstract::Double-stranded RNA has become a ubiquitous tool for inhibition of gene expression in the laboratory. If similar success could be achieved in vivo, duplex RNA might provide a new class of therapeutics capable of treating a broad spectrum of disease. Chemists and biologists developing duplex RNA as a drug have made pro...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Watts JK,Corey DR

    更新日期:2010-06-01 00:00:00

  • Peptide chemistry applied to a new family of phenothiazine-containing inhibitors of human farnesyltransferase.

    abstract::Novel phenothiazine derivatives bearing an amino acid residue were synthesized via peptide chemistry, and evaluated for their inhibitory potential on human farnesyltransferase. The phenothiazine unit proved to be an important bulky unit in the structure of the synthesized inhibitors. Propargyl ester 20 bearing a tyros...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Dumitriu GM,Ghinet A,Bîcu E,Rigo B,Dubois J,Farce A,Belei D

    更新日期:2014-07-15 00:00:00

  • 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains.

    abstract::The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacok...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lynch CL,Willoughby CA,Hale JJ,Holson EJ,Budhu RJ,Gentry AL,Rosauer KG,Caldwell CG,Chen P,Mills SG,MacCoss M,Berk S,Chen L,Chapman KT,Malkowitz L,Springer MS,Gould SL,DeMartino JA,Siciliano SJ,Cascieri MA,Carella

    更新日期:2003-01-06 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

  • Synthesis of novel 2-pyrazoline analogues with potent anti-inflammatory effect mediated by inhibition of phospholipase A2: Crystallographic, in silico docking and QSAR analysis.

    abstract::Oxidative-stress induces inflammatory diseases. Further, infections caused by drug-resistant microbial strains are on the rise. This necessitates the discovery of novel small-molecules for intervention therapy. A series of 3-(2,3-dichlorophenyl)-1-(aryl)prop-2-en-1-ones are synthesized as intermediates via Claisen-Sch...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lokeshwari DM,Achutha DK,Srinivasan B,Shivalingegowda N,Krishnappagowda LN,Kariyappa AK

    更新日期:2017-08-15 00:00:00

  • Identification of fragments targeting an alternative pocket on HIV-1 gp41 by NMR screening and similarity searching.

    abstract::The HIV-1 envelope glycoprotein gp41 fusion intermediate is a promising drug target for inhibiting viral entry. However, drug development has been impeded by challenges inherent in mediating the underlying protein-protein interaction. Here we report on the identification of fragments that bind to a C-terminal sub-pock...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chu S,Gochin M

    更新日期:2013-09-15 00:00:00

  • Shikonin derivatives: synthesis and inhibition of human telomerase.

    abstract::We synthesized DL-shikonin, shikonin, alkanin, and their cyclo-derivatives and acyl-derivatives. These compounds have low cytotoxicity, as well as inhibitory activity against the telomerase enzyme, except cyclo-derivatives. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lu Q,Liu W,Ding J,Cai J,Duan W

    更新日期:2002-05-20 00:00:00

  • Synthesis, antibacterial and cytotoxic activities of new biflorin-based hydrazones and oximes.

    abstract::Biflorin 1 is a biologically active quinone, isolated from Capraria biflora. Five new biflorin-based nitrogen derivatives were synthesized, of which two were mixtures of (E)- and (Z)- isomers: (Z)-2a, (Z)-2b, (Z)-3a, (Z)- and (E)-3b, (Z)- and (E)-3c. The antibacterial activity was investigated using the microdilution ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: da S Souza LG,Almeida MCS,Lemos TLG,Ribeiro PRV,de Brito ES,Silva VLM,Silva AMS,Braz-Filho R,Costa JGM,Rodrigues FFG,Barreto FS,de Moraes MO

    更新日期:2016-01-15 00:00:00

  • Discovery of thienopyridines as Src-family selective Lck inhibitors.

    abstract::We describe the identification, SAR, and in vivo pharmacology of a new series of Src-family selective Lck inhibitors. These thienopyridines were designed based on a desire to access the unique residues in the extended hinge region of Lck. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Abbott L,Betschmann P,Burchat A,Calderwood DJ,Davis H,Hrnciar P,Hirst GC,Li B,Morytko M,Mullen K,Yang B

    更新日期:2007-03-01 00:00:00

  • Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX.

    abstract::VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of s...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Jia C,Yang KW,Liu CC,Feng L,Xiao JM,Zhou LS,Zhang YL

    更新日期:2012-01-01 00:00:00

  • Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections.

    abstract::Current treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Washburn A,Abdeen S,Ovechkina Y,Ray AM,Stevens M,Chitre S,Sivinski J,Park Y,Johnson J,Hoang QQ,Chapman E,Parish T,Johnson SM

    更新日期:2019-07-01 00:00:00

  • Structure based medicinal chemistry approach to develop 4-methyl-7-deazaadenine carbocyclic nucleosides as anti-HCV agent.

    abstract::The structure-based approaches were implemented to design and rationally select the molecules for synthesis and anti-HCV activity evaluation. The systematic structure-activity relationships of previously discovered molecules (types I, II, III) were analyzed to design new molecules (type IV) by bioisosteric replacement...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Thiyagarajan A,Salim MT,Balaraju T,Bal C,Baba M,Sharon A

    更新日期:2012-12-15 00:00:00

  • Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2. Structure-activity relationships of the 7- and 5-, 6-, 8-positions.

    abstract::As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of 4-aryl-4H-chromenes with modifications at the 7- and 5-, 6-, 8-positions. It was found that a small hydrophobic group, such as NMe2, NH2, NHEt, and OMe, is preferred at...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kemnitzer W,Kasibhatla S,Jiang S,Zhang H,Zhao J,Jia S,Xu L,Crogan-Grundy C,Denis R,Barriault N,Vaillancourt L,Charron S,Dodd J,Attardo G,Labrecque D,Lamothe S,Gourdeau H,Tseng B,Drewe J,Cai SX

    更新日期:2005-11-01 00:00:00

  • Design, synthesis and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in diabetes.

    abstract::We report the design, synthesis, biological activity and docking studies of series of novel pyrazolo[3,4-d]pyrimidinones as DPP-IV inhibitors in diabetes. Molecules were synthesized and evaluated for their DPP-IV inhibition activity. Compounds 5e, 5k, 5o and 6a were found to be potent inhibitors of DPP-IV enzyme. Amon...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sagar SR,Agarwal JK,Pandya DH,Dash RP,Nivsarkar M,Vasu KK

    更新日期:2015-10-15 00:00:00