Design and synthesis of tetracyclic nonpeptidic biaryl nitrile inhibitors of cathepsin K.


:The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of osteoporosis.


Bioorg Med Chem Lett


Setti EL,Venkatraman S,Palmer JT,Xie X,Cheung H,Yu W,Wesolowski G,Robichaud J




Has Abstract


2006-08-15 00:00:00














  • Soluble polyphenols: synthesis and bioavailability of 3,4',5-tri(alpha-D-glucose-3-O-succinyl) resveratrol.

    abstract::We report the development of a chemical modification method of general applicability to polyphenols, which increases solubility to influence absorption. Glucosyl groups were added to the resveratrol kernel via a succinate linker, yielding 3,4',5-tri-(alpha-D-glucose-3-O-succinyl) resveratrol. The construct was only sl...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Biasutto L,Marotta E,Bradaschia A,Fallica M,Mattarei A,Garbisa S,Zoratti M,Paradisi C

    更新日期:2009-12-01 00:00:00

  • Benzimidazolone as potent chymase inhibitor: modulation of reactive metabolite formation in the hydrophobic (P1) region.

    abstract::A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P(1) hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P(1) moiety. Replacement of the benzothiophene with different heterocyclic sy...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lo HY,Nemoto PA,Kim JM,Hao MH,Qian KC,Farrow NA,Albaugh DR,Fowler DM,Schneiderman RD,Michael August E,Martin L,Hill-Drzewi M,Pullen SS,Takahashi H,De Lombaert S

    更新日期:2011-08-01 00:00:00

  • Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 5.

    abstract::A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Takeuchi K,Kohn TJ,Honigschmidt NA,Rocco VP,Spinazze PG,Hemrick-Luecke SK,Thompson LK,Evans DC,Rasmussen K,Koger D,Lodge D,Martin LJ,Shaw J,Threlkeld PG,Wong DT

    更新日期:2006-05-01 00:00:00

  • Novel phenylpiperazine derivatives as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity.

    abstract::Phenylpiperazine derivatives were synthesized as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity. Lead optimization led to compound 5k having the potent regulatory activity and demonstrating remarkable protective effects against the lethal challenge of LPS in mice. suggesting that 5k ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hanano T,Adachi K,Aoki Y,Morimoto H,Naka Y,Hisadome M,Fukuda T,Sumichika H

    更新日期:2000-05-01 00:00:00

  • Azaterphenyl diamidines as antileishmanial agents.

    abstract::Eighteen diamidino azaterphenyls and analogues were evaluated as anti-leishmanials; nine of the compounds gave IC50 values less than 1 microM, five exhibited values less than 0.40 microM, and two gave values less than 0.10 microM in a Leishmania donovani axenic amastigote assay. The activity of the diamidines strongly...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hu L,Arafa RK,Ismail MA,Wenzler T,Brun R,Munde M,Wilson WD,Nzimiro S,Samyesudhas S,Werbovetz KA,Boykin DW

    更新日期:2008-01-01 00:00:00

  • The synthesis and structure-activity relationships of 4-aryl-3-aminoquinolin-2-ones: a new class of calcium-dependent, large conductance, potassium (maxi-K) channel openers targeted for post-stroke neuroprotection.

    abstract::A series of 4-aryl-3-aminoquinoline-2-one derivatives was synthesized and evaluated as activators of the cloned maxi-K channel mSlo (hSlo) expressed in Xenopus laevis oocytes using electrophysiological methods. A brain penetrable activator of maxi-K channels was identified and shown to be significantly active in the M...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hewawasam P,Fan W,Knipe J,Moon SL,Boissard CG,Gribkoff VK,Starrett JE

    更新日期:2002-07-08 00:00:00

  • Synthesis of rare sugars with L-fuculose-1-phosphate aldolase (FucA) from Thermus thermophilus HB8.

    abstract::We report herein a one-pot four-enzyme approach for the synthesis of the rare sugars d-psicose, d-sorbose, l-tagatose, and l-fructose with aldolase FucA from a thermophilic source (Thermus thermophilus HB8). Importantly, the cheap starting material DL-GP (DL-glycerol 3-phosphate), was used to significantly reduce the ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li Z,Cai L,Qi Q,Styslinger TJ,Zhao G,Wang PG

    更新日期:2011-09-01 00:00:00

  • SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

    abstract::COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Mantell SJ,Stephenson PT,Monaghan SM,Maw GN,Trevethick MA,Yeadon M,Walker DK,Selby MD,Batchelor DV,Rozze S,Chavaroche H,Lemaitre A,Wright KN,Whitlock L,Stuart EF,Wright PA,Macintyre F

    更新日期:2009-08-01 00:00:00

  • Antiangiogenic properties of substituted (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol/one analogs and their derivatives.

    abstract::In the past half century research efforts have defined a critical role for angiogenesis in tumor growth and metastasis. We previously reported that inhibition of a novel target, ENOX1, by a (Z)-2-benzylindol-3-ylmethylene) quinuclidin-3-ol, suppressed tumor angiogenesis. The present study was undertaken in order to es...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Venkateswaran A,Reddy YT,Sonar VN,Muthusamy V,Crooks PA,Freeman ML,Sekhar KR

    更新日期:2010-12-15 00:00:00

  • Novel antifungals based on 4-substituted imidazole: solid-phase synthesis of substituted aryl sulfonamides towards optimization of in vitro activity.

    abstract::The in vitro activity of novel 4-substituted imidazole antifungals was optimized by solid-phase chemistry and parallel synthesis. Potent yeast-selective as well as broad-spectrum antifungal compounds (32 and 20) were discovered. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Saha AK,Liu L,Marichal P,Odds F

    更新日期:2000-12-18 00:00:00

  • Efficient synthesis and biological evaluation of some 2,4-diamino-furo[2,3-d]pyrimidine derivatives.

    abstract::The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with ammonia to give ethyl 3,4-dihydro-6-methyl-4-oxo-2-arylamino-furo[2,3-d]pyrimidine-5-carboxylate 3. Further reaction of 3 with POCl(3) and various amines generated ethyl 4-alkylamino-2-arylamino-6-meth...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hu YG,Wang Y,Du SM,Chen XB,Ding MW

    更新日期:2010-11-01 00:00:00

  • 2,2-Dimethyl-4,5-diaryl-3(2H)furanone derivatives as selective cyclo-oxygenase-2 inhibitors.

    abstract::A series of 2,2-dimethyl-5-[4-(methylsulfonyl)phenyl]-4-phenyl-3(2H)furanones was prepared and evaluated for their ability to inhibit cyclo-oxygenase-2 (COX-2). ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Shin SS,Noh MS,Byun YJ,Choi JK,Kim JY,Lim KM,Ha JY,Kim JK,Lee CH,Chung S

    更新日期:2001-01-22 00:00:00

  • Flavonoids from Woodfordia fruticosa as potential SmltD inhibitors in the alternative biosynthetic pathway of peptidoglycan.

    abstract::SmltD is an ATP-dependent ligase that catalyzes the condensation of UDP-MurNAc-l-Ala and l-Glu to form UDP-MurNAc-l-Ala-l-Glu, in the newly discovered peptidoglycan biosynthesis pathway of a Gram-negative multiple-drug-resistant pathogen, Stenotrophomonas maltophilia. Phytochemical investigation of the 70% ethanol ext...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lee YE,Kodama T,Win NN,Ki DW,Hoang NN,Wong CP,Lae KZW,Ngwe H,Dairi T,Morita H

    更新日期:2021-01-15 00:00:00

  • Synthesis and biological evaluation of [4-(2-phenylethenesulfonylmethyl)phenyl]-quinazolin-4-yl-amines as orally active anti-cancer agents.

    abstract::A new series of [4-(2-phenylethenesulfonylmethyl)phenyl]quinazolin-4-yl-amines was prepared and tested for its in vitro cytotoxic activity against a panel of 12 human cancer cell lines. Compounds 9, 15, 24 and 31 showed good in vitro activity and were further tested for their in vivo efficacy in the HT-29 human colon ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sharma VM,Adi Seshu KV,Chandra Sekhar V,Madan S,Vishnu B,Babu PA,Vamsee Krishna C,Sreenu J,Ravi Krishna V,Venkateswarlu A,Rajagopal S,Ajaykumar R,Kumar TS

    更新日期:2004-01-05 00:00:00

  • Design and synthesis of 3,4-dihydro-1H-[1]-benzothieno[2,3-c]pyran and 3,4-dihydro-1H-pyrano[3,4-b]benzofuran derivatives as non-nucleoside inhibitors of HCV NS5B RNA dependent RNA polymerase.

    abstract::A novel class of HCV NS5B RNA dependent RNA polymerase inhibitors containing 3,4-dihydro-1H-[1]-benzothieno[2,3-c]pyran and 3,4-dihydro-1H-pyrano[3,4-b]benzofuran scaffolds were designed and synthesized. Optimization of the alkyl substituent in the pyran ring showed preference for an n-propyl group, while 5,8-disubsti...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Gopalsamy A,Aplasca A,Ciszewski G,Park K,Ellingboe JW,Orlowski M,Feld B,Howe AY

    更新日期:2006-01-15 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

  • New strigolactone mimics: structure-activity relationship and mode of action as germinating stimulants for parasitic weeds.

    abstract::Strigolactones (SLs) are new plant hormones with varies important bio-functions. This Letter deals with germination of seeds of parasitic weeds. Natural SLs have a too complex structure for synthesis. Therefore, there is an active search for SL analogues and mimics with a simpler structure with retention of activity. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zwanenburg B,Nayak SK,Charnikhova TV,Bouwmeester HJ

    更新日期:2013-09-15 00:00:00

  • Synthesis and structure-activity relationship of 3,4'-bispyridinylethylenes: discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer.

    abstract::Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li Q,Woods KW,Thomas S,Zhu GD,Packard G,Fisher J,Li T,Gong J,Dinges J,Song X,Abrams J,Luo Y,Johnson EF,Shi Y,Liu X,Klinghofer V,Des Jong R,Oltersdorf T,Stoll VS,Jakob CG,Rosenberg SH,Giranda VL

    更新日期:2006-04-01 00:00:00

  • Thiophene-based vitronectin receptor antagonists.

    abstract::A series of alpha(v)beta(3) antagonists based on a thiophene scaffold were synthesized via two routes and evaluated for in vitro biological activity. We have identified several structurally similar antagonists with different selectivities towards alpha(IIb)beta(3), alpha(v)beta(5) and alpha(5)beta(1) at the cellular l...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bubenik M,Meerovitch K,Bergeron F,Attardo G,Chan L

    更新日期:2003-02-10 00:00:00

  • Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine.

    abstract::The naturally occurring aporphine alkaloid nantenine, has been shown to antagonize behavioral and physiological effects of MDMA in mice. We have synthesized (+/-)-nantenine via an oxidative cyclization reaction with PIFA and evaluated its binding profile against a panel of CNS targets. To begin to understand the impor...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Legendre O,Pecic S,Chaudhary S,Zimmerman SM,Fantegrossi WE,Harding WW

    更新日期:2010-01-15 00:00:00

  • Flavonoids: structural requirements for antiproliferative activity on breast cancer cells.

    abstract::Several classes of flavonoids (flavones, flavanones, 2'-hydroxychalcones and flavan-4-ols) having a variety of substituents on A ring were investigated for their antiproliferative activity against MCF-7 human breast cancer cells. Structure-activity relationships of these compounds were discussed. 2'-hydroxychalcones a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Pouget C,Lauthier F,Simon A,Fagnere C,Basly JP,Delage C,Chulia AJ

    更新日期:2001-12-17 00:00:00

  • Solid-phase synthesis and pharmacological evaluation of novel nucleoside-tethered dinuclear platinum(II) complexes.

    abstract::Three novel inosine-based dinuclear platinum complexes have been synthesized via a solid-phase strategy. In these compounds, the metal is linked both to the N-7 of the purine nucleus and to the terminal amine group of a hexylamine side chain installed on N-1. Cis- or trans- diamine as well as ethylenediamine ligands a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: D'Errico S,Oliviero G,Piccialli V,Amato J,Borbone N,D'Atri V,D'Alessio F,Di Noto R,Ruffo F,Salvatore F,Piccialli G

    更新日期:2011-10-01 00:00:00

  • Discovery of novel, orally active dual NK1/NK2 antagonists.

    abstract::Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, respectively). In functi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bernstein PR,Aharony D,Albert JS,Andisik D,Barthlow HG,Bialecki R,Davenport T,Dedinas RF,Dembofsky BT,Koether G,Kosmider BJ,Kirkland K,Ohnmacht CJ,Potts W,Rumsey WL,Shen L,Shenvi A,Sherwood S,Stollman D,Russell K

    更新日期:2001-10-22 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

  • Heterocyclic sulfoxide and sulfone inhibitors of fatty acid amide hydrolase.

    abstract::A novel series of heterocyclic sulfoxides and sulfones was prepared and examined as potential inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for inactivation of neuromodulating fatty acid amides including anandamide and oleamide. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Du W,Hardouin C,Cheng H,Hwang I,Boger DL

    更新日期:2005-01-03 00:00:00

  • The preparation of 2,6-disubstituted pyridinyl phosphine oxides as novel anti-cancer agents.

    abstract::A series of 2,6-dimethoxylpyridinyl phosphine oxides have been synthesized and examined for their antitumor activity. 2,6-Dimethoxy-3-phenyl-4-diphenylphosphinoylpyridine 2 has been employed as the lead compound for this study. We found out that the presence of phosphine oxide on the 2,6-dimethoxylpyridine ring is imp...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lam KH,Gambari R,Yuen MC,Kan CW,Chan P,Xu L,Tang W,Chui CH,Cheng GY,Wong RS,Lau FY,Tong CS,Chan AK,Lai PB,Kok SH,Cheng CH,Chan AS,Tang JC

    更新日期:2009-04-15 00:00:00

  • Highly potent, broadly active antifungal agents for the treatment of invasive fungal infections.

    abstract::Invasive fungal infections have become an important healthcare issue due in large part to high mortality rates under standard of care (SOC) therapies creating an urgent need for new and effective anti-fungal agents. We have developed a series of non-peptide, structurally-constrained analogs of host defence proteins th...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Baugh SDP,Chaly A,Weaver DG,Pelletier JC,Thanna S,Freeman KB,Reitz AB,Scott RW

    更新日期:2020-12-13 00:00:00

  • Palbinone and triterpenes from Moutan Cortex (Paeonia suffruticosa, Paeoniaceae) stimulate glucose uptake and glycogen synthesis via activation of AMPK in insulin-resistant human HepG2 Cells.

    abstract::Moutan Cortex is a well-known herb in traditional Korean, Chinese, and Japanese anti-diabetic formulae. In the current study, we investigated the metabolic effects of isolated triterpenes (1-7) in HepG2 cells under high glucose conditions. These compounds remakably stimulated AMP-activated protein kinase (AMPK), GSK-3...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ha do T,Tuan DT,Thu NB,Nhiem NX,Ngoc TM,Yim N,Bae K

    更新日期:2009-10-01 00:00:00

  • 3-cyanoindole-based inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.

    abstract::A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structu...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Dhar TG,Shen Z,Gu HH,Chen P,Norris D,Watterson SH,Ballentine SK,Fleener CA,Rouleau KA,Barrish JC,Townsend R,Hollenbaugh DL,Iwanowicz EJ

    更新日期:2003-10-20 00:00:00

  • Insights into the substrate specificity of the MutT pyrophosphohydrolase using structural analogues of 8-oxo-2'-deoxyguanosine nucleotide.

    abstract::The bacterial repair enzyme MutT hydrolyzes the damaged nucleotide OdGTP (the 5'-triphosphate derivative of 8-oxo-2'-deoxyguanosine; OdG), which is a known mutagen and has been linked to antibacterial action. Previous work has indicated important roles for the C8-oxygen, N7-hydrogen, and C2-exocyclic amine during OdGT...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hamm ML,McFadden EJ,Ghio M,Lindell MA,Gerien KS,O'Handley SF

    更新日期:2016-04-15 00:00:00