Chroman-3-amides as potent Rho kinase inhibitors.


:Inhibition of Rho kinase (ROCK) is an attractive strategy for the treatment of diseases such as hypertension, glaucoma, and cancer. Here we report chroman-3-amides as highly potent ROCK inhibitors with sufficient kinase selectivity, excellent cell activity, good microsomal stability, and desirable pharmacokinetic properties for study as potential therapeutic agents.


Bioorg Med Chem Lett


Chen YT,Bannister TD,Weiser A,Griffin E,Lin L,Ruiz C,Cameron MD,Schürer S,Duckett D,Schröter T,LoGrasso P,Feng Y




Has Abstract


2008-12-15 00:00:00














  • New C-23 modified of silybin and 2,3-dehydrosilybin: synthesis and preliminary evaluation of antioxidant properties.

    abstract::Silybin is the major flavonolignan of silymarin and it displays a plethora of biological effects, generally ascribed to its antioxidant properties. Herein we shall describe an efficient synthetic strategy to obtain a variety of new and more water-soluble silybin and 2,3-dehydrosilybin (DHS) derivatives in which the 23...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zarrelli A,Sgambato A,Petito V,De Napoli L,Previtera L,Di Fabio G

    更新日期:2011-08-01 00:00:00

  • Thiazolone-acylsulfonamides as novel HCV NS5B polymerase allosteric inhibitors: convergence of structure-based drug design and X-ray crystallographic study.

    abstract::A novel series of thiazolone-acylsulfonamides were designed as HCV NS5B polymerase allosteric inhibitors. The structure based drug designs (SBDD) were guided by docking results that revealed the potential to explore an additional pocket in the allosteric site. In particular, the designed molecules contain moieties of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yan S,Appleby T,Larson G,Wu JZ,Hamatake RK,Hong Z,Yao N

    更新日期:2007-04-01 00:00:00

  • Design and synthesis of new bis-pyridinium oxime reactivators for acetylcholinesterase inhibited by organophosphorous nerve agents.

    abstract::New bis-pyridinium oxime reactivators connected with a CH(2)CH(2)OCH(2)CH(2) linker between two pyridinium rings were designed and synthesized. In the test of their potency to reactivate AChE inhibited by cyclosarin, the bis-pyridinium oxime 6b achieved reactivation potency higher than 10% at the lower concentration 1...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kim TH,Kuca K,Jun D,Jung YS

    更新日期:2005-06-02 00:00:00

  • Synthesis and 5 alpha-reductase inhibitory activities of benzofuran derivatives with a carbamoyl group.

    abstract::A series of 2-phenylbenzofuran derivatives with a diphenylmethylcarbamoyl group at the 5 or 6 position of the benzofuran ring were synthesized and evaluated for rat and human testosterone 5 alpha-reductase inhibitory activities in vitro. They had inhibitory activities against both enzymes and the 6-carbamoyl derivativ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ishibashi K,Nakajima K,Sugioka Y,Sugiyama M,Hamada T,Horikoshi H,Nishi T

    更新日期:1998-03-17 00:00:00

  • Discovery of a series of aminopiperidines as novel iNOS inhibitors.

    abstract::Nitric oxide (NO), a mediator of various physiological and pathophysiological processes, is synthesized by three isozymes of nitric oxide synthase (NOS). Potential candidate clinical drugs should be devoid of inhibitory activity against endothelial NOS (eNOS), since eNOS plays an important role in maintaining normal b...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Le Bourdonnec B,Leister LK,Ajello CA,Cassel JA,Seida PR,O'Hare H,Gu M,Chu GH,Tuthill PA,DeHaven RN,Dolle RE

    更新日期:2008-01-01 00:00:00

  • Synthesis and pharmacological evaluation of the stereoisomers of 3-carba cyclic-phosphatidic acid.

    abstract::Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a five-membered ring with the sn-3 phosphate. Here, we describe the synthesis of R-3-CCPA and S-3-CCPA along with their pharmacological properties as inhibitors of lysophospholipase D/aut...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Gupte R,Siddam A,Lu Y,Li W,Fujiwara Y,Panupinthu N,Pham TC,Baker DL,Parrill AL,Gotoh M,Murakami-Murofushi K,Kobayashi S,Mills GB,Tigyi G,Miller DD

    更新日期:2010-12-15 00:00:00

  • Antimitotic activity and reversal of breast cancer resistance protein-mediated drug resistance by stilbenoids from Bletilla striata.

    abstract::Eight stilbenoids, 1-(p-hydroxybenzyl)-4,8-dimethoxyphenanthrene-2,7-diol (1), 2,7-dihydroxy-1,3-bis(p-hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene (2), 4,7-dihydroxy-1-(p-hydroxybenzyl)-2-methoxy-9,10-dihydrophenanthrene (3), 3,3'-dihydroxy-2',6'-bis(p-hydroxybenzyl)-5-methoxybibenzyl (4), 3',5-dihydroxy-2-(p-hy...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Morita H,Koyama K,Sugimoto Y,Kobayashi J

    更新日期:2005-02-15 00:00:00

  • 4-arylphthalazin-1(2H)-one derivatives as potent antagonists of the melanin concentrating hormone receptor 1 (MCH-R1).

    abstract::A novel series of 4-arylphthalazin-1(2H)-one linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of an extensive SAR study probing the effects of substituents on the 4-arylphthalazin-1(2H)-one C-4 aryl group led to the identification of the 4-(3,4-difluorophenyl) derivative as a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lim CJ,Kim SH,Lee BH,Oh KS,Yi KY

    更新日期:2012-01-01 00:00:00

  • Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands.

    abstract::A series of new 9-O-substituted berberine derivatives (4a-j) as telomeric quadruplex ligands was synthesized and evaluated. The results from biophysical and biochemical assay indicated that introducing of positive charged aza-aromatic terminal group into the side chain of 9-position of berberine significantly improved...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ma Y,Ou TM,Tan JH,Hou JQ,Huang SL,Gu LQ,Huang ZS

    更新日期:2009-07-01 00:00:00

  • Modified 3-alkyl-1,8-dibenzylxanthines as GTP-competitive inhibitors of phosphoenolpyruvate carboxykinase.

    abstract::The first non-substrate like inhibitors of human cytosolic phosphoenolpyruvate carboxykinase (PEPCK) competitive with GTP are reported. An effort to discover orally active compounds that improve glucose homeostasis in Type 2 diabetics by reversibly inhibiting PEPCK led to the discovery of 1-allyl-3-butyl-8-methylxanth...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Foley LH,Wang P,Dunten P,Ramsey G,Gubler ML,Wertheimer SJ

    更新日期:2003-10-20 00:00:00

  • Structure-activity relationships of untenone A and its derivatives for inhibition of DNA polymerases.

    abstract::We found that untenone A and mannzamenone A inhibit mammalian DNA polymerases alpha and beta, and human terminal deoxynucleotidyl transferase (TdT). The syntheses of both compounds and the structure-activity relationships of untenone A derivatives are described. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Saito F,Takeuchi R,Kamino T,Kuramochi K,Sugawara F,Sakaguchi K,Kobayashi S

    更新日期:2004-04-19 00:00:00

  • Yohimbine dimers exhibiting binding selectivities for human alpha2a- versus alpha2b-adrenergic receptors.

    abstract::A series of yohimbine dimers was prepared and evaluated at the human alpha2a- and alpha2b-adrenergic receptors (ARs) expressed in Chinese hamster ovary (CHO) cells. All dimers display higher binding selectivities for alpha2a versus alpha2b subtype than yohimbine, and four compounds (3d, 3e, 3g and 3i) represent the mo...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zheng W,Lei L,Lalchandani S,Sun G,Feller DR,Miller DD

    更新日期:2000-04-03 00:00:00

  • Synthesis and antitubercular activity of monocyclic nitroimidazoles: insights from econazole.

    abstract::We have designed and synthesized econazole-derived nitroimidazoles to investigate the antitubercular activity of the nitroimidazole compounds. The introduction of a nitro group at the 4-position of the imidazole on econazole abolished the antitubercular activity. However, alcoholic nitroimidazoles 4 and 6 compounds we...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lee SH,Kim S,Yun MH,Lee YS,Cho SN,Oh T,Kim P

    更新日期:2011-03-01 00:00:00

  • Reaction of naphthoquinones with substituted nitromethanes. Facile synthesis and antifungal activity of naphtho[2,3-d]isoxazole-4,9-diones.

    abstract::We report here a simple entry into naphtho[2,3-d]isoxazole-4,9-dione system containing a EWG in position 3 using the readily available 2,3-dichloro-1,4-naphthoquinone and nitromethyl derivatives in the presence of base. Antifungal activity of synthesised naphthoquinones was evaluated against ATCC and PYCC reference st...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Santos MM,Faria N,Iley J,Coles SJ,Hursthouse MB,Martins ML,Moreira R

    更新日期:2010-01-01 00:00:00

  • Carbonic anhydrase inhibitors: Selective inhibition of the extracellular, tumor-associated isoforms IX and XII over isozymes I and II with glycosyl-thioureido-sulfonamides.

    abstract::A series of glycosyl-thioureido sulfonamides incorporating glucosamine, galactosamine, and mannosamine tails, and sulfanilamide, halogenosulfanilamide, and metanilamide heads was synthesized. Many of the new compounds showed micromolar-submicromolar affinity for the inhibition of the cytosolic isoforms I and II of the...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Smaine FZ,Winum JY,Montero JL,Regainia Z,Vullo D,Scozzafava A,Supuran CT

    更新日期:2007-09-15 00:00:00

  • Discovery and optimization of (R)-prolinol-derived agonists of the Growth Hormone Secretagogue receptor (GHSR).

    abstract::The discovery and optimization of a novel series of prolinol-derived GHSR agonists is described. This series emerged from a 11,520-member solid-phase library targeting the GPCR protein superfamily, and the rapid optimization of low micromolar hits into single-digit nanomolar leads can be attributed to the solid-phase ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zhai W,Flynn N,Longhi DA,Tino JA,Murphy BJ,Slusarchyk D,Gordon DA,Pendri A,Shi S,Stoffel R,Ma B,Sofia MJ,Gerritz SW

    更新日期:2008-09-15 00:00:00

  • Dihydropyrazolopyrimidine inhibitors of K(V)1.5 (I(Kur)).

    abstract::A series of dihydropyrazolopyrimidine inhibitors of K(V)1.5 (I(Kur)) have been identified. The synthesis, structure-activity relationships and selectivity against several other ion channels are described. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Vaccaro W,Huynh T,Lloyd J,Atwal K,Finlay HJ,Levesque P,Conder ML,Jenkins-West T,Shi H,Sun L

    更新日期:2008-12-15 00:00:00

  • Structure-based optimisation of 2-aminobenzylstatine derivatives: potent and selective inhibitors of the chymotrypsin-like activity of the human 20S proteasome.

    abstract::We have identified 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the human 20S proteasome. A structure-based optimisation approach has allowed us to improve the potency of this structural class of proteasome inhibitors from micromolar to nanomolar level. The new derivat...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Furet P,Imbach P,Fuerst P,Lang M,Noorani M,Zimmermann J,García-Echeverría C

    更新日期:2002-05-20 00:00:00

  • Synthesis and evaluation of cholecystokinin trimers: a multivalent approach to pancreatic cancer detection and treatment.

    abstract::In the quest for novel tools for early detection and treatment of cancer, we propose the use of multimers targeting overexpressed receptors at the cancer cell surface. Indeed, multimers are prone to create multivalent interactions, more potent and specific than their corresponding monovalent versions, thus enabling th...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Brabez N,Nguyen KL,Saunders K,Lacy R,Xu L,Gillies RJ,Lynch RM,Chassaing G,Lavielle S,Hruby VJ

    更新日期:2013-04-15 00:00:00

  • Selective inhibition of monoamine oxidase A by chelerythrine, an isoquinoline alkaloid.

    abstract::Chelerythrine, an isoquinoline alkaloid isolated from the herbaceous perennial Chelidonium majus, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A) with an IC50 value of 0.55 µM. Chelerythrine was a reversible competitive MAO-A inhibitor (Ki = 0.22 µM) with a pot...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Baek SC,Ryu HW,Kang MG,Lee H,Park D,Cho ML,Oh SR,Kim H

    更新日期:2018-08-01 00:00:00

  • Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide.

    abstract::A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3-triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferat...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Altimari JM,Niranjan B,Risbridger GP,Schweiker SS,Lohning AE,Henderson LC

    更新日期:2014-11-01 00:00:00

  • Enediynyl peptides and iso-coumarinyl methyl sulfones as inhibitors of proprotein convertases PCSK8/SKI-1/S1P and PCSK4/PC4: Design, synthesis and biological evaluations.

    abstract::The proprotein convertases PCSK8 and PCSK4 are, respectively, the 8th and 4th members of Ca(+2)-dependent serine endoprotease of Proprotein Convertase Subtilisin Kexin (PCSK) super family structurally related to the bacterial subtilisin and yeast kexin. The membrane bound PCSK8 (also called SKI-1 or S1P) is implicated...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Basak A,Goswami M,Rajkumar A,Mitra T,Majumdar S,O'Reilly P,Bdour HM,Trudeau VL,Basak A

    更新日期:2015-01-01 00:00:00

  • SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.

    abstract::We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Adva...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Forsyth T,Kearney PC,Kim BG,Johnson HW,Aay N,Arcalas A,Brown DS,Chan V,Chen J,Du H,Epshteyn S,Galan AA,Huynh TP,Ibrahim MA,Kane B,Koltun ES,Mann G,Meyr LE,Lee MS,Lewis GL,Noguchi RT,Pack M,Ridgway BH,Shi X,

    更新日期:2012-12-15 00:00:00

  • The food-grade antimicrobial xanthorrhizol targets the enoyl-ACP reductase (FabI) in Escherichia coli.

    abstract::Xanthorrhizol, isolated from the Indonesian Java turmeric Curcuma xanthorrhiza, displays broad-spectrum antibacterial activity. We report herein the evidence that mechanism of action of xanthorrhizol may involve FabI, an enoyl-(ACP) reductase, inhibition. The predicted Y156V substitution in the FabI enzyme promoted xa...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yogiara,Mordukhova EA,Kim D,Kim WG,Hwang JK,Pan JG

    更新日期:2020-12-15 00:00:00

  • Identification and structure-activity relationship studies of 3-methylene-2-norbornanone as potent anti-proliferative agents presumably working through p53 mediated apoptosis.

    abstract::We have identified a novel series of alpha-methylene carbonyl compounds through structure-activity relationship (SAR) studies with high levels of anti-proliferative activities. The lead molecule, 3-methylene-2-norbornanone (3) showed potent activity (LC(50)=3-8 microM) against mutant p53 cell types and many fold selec...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Reddy NL,Hill J,Ye L,Fernandes PB,Stout DM

    更新日期:2004-11-15 00:00:00

  • Structural measurements and cell line studies of the copper-PEG-Rifampicin complex against Mycobacterium tuberculosis.

    abstract::The bacterium responsible for tuberculosis is increasing its resistance to antibiotics resulting in new multidrug-resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). In this study, several analytical techniques including NMR, FT-ICR, MALDI-MS, LC-MS and UV/Vis are used t...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Manning T,Mikula R,Wylie G,Phillips D,Jarvis J,Zhang F

    更新日期:2015-02-01 00:00:00

  • Development of novel tail-modified anandamide analogs.

    abstract::To explore the hydrophobic groove subsite within the CB1 cannabinoid receptor we have designed and synthesized a group of tail-substituted anandamide analogs. Our design involves the introduction of aryl or heterocyclic ring as terminal substituents that are connected to the last cis-arachidonyl double bond through al...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yao F,Li C,Vadivel SK,Bowman AL,Makriyannis A

    更新日期:2008-11-15 00:00:00

  • Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.

    abstract::Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in th...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ray P,Wright J,Adam J,Bennett J,Boucharens S,Black D,Cook A,Brown AR,Epemolu O,Fletcher D,Haunso A,Huggett M,Jones P,Laats S,Lyons A,Mestres J,de Man J,Morphy R,Rankovic Z,Sherborne B,Sherry L,van Straten N,We

    更新日期:2011-01-01 00:00:00

  • 3-heterocyclyl quinolone inhibitors of the HCV NS5B polymerase.

    abstract::The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key anal...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kumar DV,Rai R,Brameld KA,Riggs J,Somoza JR,Rajagopalan R,Janc JW,Xia YM,Ton TL,Hu H,Lehoux I,Ho JD,Young WB,Hart B,Green MJ

    更新日期:2012-01-01 00:00:00

  • Discovery and optimization of a biphenylacetic acid series of prostaglandin D2 receptor DP2 antagonists with efficacy in a murine model of allergic rhinitis.

    abstract::Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D(2) receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eos...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Scott JM,Baccei C,Bain G,Broadhead A,Evans JF,Fagan P,Hutchinson JH,King C,Lorrain DS,Lee C,Prasit P,Prodanovich P,Santini A,Stearns BA

    更新日期:2011-11-01 00:00:00