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














  • Identification of blapsins A and B as potent small-molecule 14-3-3 inhibitors from the insect Blaps japanensis.

    abstract::In this study, we report three novel naturally occurring compounds, blapsins A (1) and B (2), and blapsamide (3) from the ethanol extract of the stink beetle, Blaps japanensis. The structures of these compounds were determined using spectroscopic methods. Compound 3 is a phenolic compound bearing a formamido group in ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yan YM,Dai HQ,Du Y,Schneider B,Guo H,Li DP,Zhang LX,Fu H,Dong XP,Cheng YX

    更新日期:2012-06-15 00:00:00

  • Macrocyclic factor XIa inhibitors.

    abstract::A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang C,Corte JR,Rossi KA,Bozarth JM,Wu Y,Sheriff S,Myers JE Jr,Luettgen JM,Seiffert DA,Wexler RR,Quan ML

    更新日期:2017-09-01 00:00:00

  • Discovery of phenanthridine analogues as novel chemical probes disrupting the binding of DNA to ΔFosB homodimers and ΔFosB/JunD heterodimers.

    abstract::The transcription factor ΔFosB accumulates in response to chronic insults such as drugs of abuse, L-3,4-dihydroxyphenylalanine (l-DOPA) or stress in specific regions of the brain, triggering long lasting neural and behavioral changes that underlie aspects of drug addiction, dyskinesia, and depression. Thus, small mole...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li Y,Liu Z,Aglyamova G,Chen J,Chen H,Bhandari M,White MA,Rudenko G,Zhou J

    更新日期:2020-08-15 00:00:00

  • Decreasing the CYP2D6 contribution to metabolism of a CK1ε inhibitor.

    abstract::Our internal casein kinase 1ε lead inhibitor, compound 1 was partially cleared by the polymorphic cytochrome P450 2D6. CYP2D6 involvement in metabolism implies more extensive clinical trials. We therefore wanted to reduce the contribution to clearance by this enzyme. We utilized metabolism reports for compound 1 perfo...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Vaz RJ,Li Y,Metz M,Yang D,Shen H,Munson M

    更新日期:2018-12-15 00:00:00

  • C1 and N5 derivatives of cerpegin: synthesis of a new series based on structure-activity relationships to optimize their inhibitory effect on 20S proteasome.

    abstract::Thirty-two new derivatives of cerpegin (1,1,5-trimethylfuro[3,4-c]pyridine-3,4-dione) were designed and synthesized in high yield by a new method, combining several C(1) and N(5) substituents. All compounds were tested for their inhibitory effect on the CT-L, T-L and PA proteolytic activities of a purified mammalian 2...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hovhannisyan A,Pham TH,Bouvier D,Qin L,Melikyan G,Reboud-Ravaux M,Bouvier-Durand M

    更新日期:2013-05-01 00:00:00

  • Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA.

    abstract::This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zhao Z,Wisnoski DD,O'Brien JA,Lemaire W,Williams DL Jr,Jacobson MA,Wittman M,Ha SN,Schaffhauser H,Sur C,Pettibone DJ,Duggan ME,Conn PJ,Hartman GD,Lindsley CW

    更新日期:2007-03-01 00:00:00

  • Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation.

    abstract::Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic beta-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K(i) 1.8 nM) and cellular (IC(50)=1 ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ghosh AK,Kumaragurubaran N,Hong L,Kulkarni S,Xu X,Miller HB,Reddy DS,Weerasena V,Turner R,Chang W,Koelsch G,Tang J

    更新日期:2008-02-01 00:00:00

  • Bis-pyridiumaldoxime reactivators connected with CH2O(CH2)n OCH2 linkers between pyridinium rings and their reactivity against VX.

    abstract::New bis-pyridinium oxime reactivators connected with CH2O(CH2)n OCH2 linkers between two pyridinium rings were designed and synthesized, and their reactivation potency was evaluated for AChE inhibited by organophosphorus VX agent. Among the prepared compounds, 1,2-dimethoxy-ethylene-bis-N,N'-4-pyridiumaldoxime dichlor...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Oh KA,Yang GY,Jun D,Kuca K,Jung YS

    更新日期:2006-09-15 00:00:00

  • Synthesis and methemoglobin toxicity of the amides of 6/7 mono or disubstituted quinolone.

    abstract::A series of 6/7-mono and disubstituted quinolone-3-carboxamide derivatives (1-12) were synthesized and their in vitro methemoglobin producing capacity have been delineated. The compounds 5, 6, 9 and 10 showed minimum methemoglobin toxicity. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Srivastava S,Srivastava SK,Shukla A,Chauhan PM,Puri SK,Bhaduri AP,Pandey VC

    更新日期:1999-01-04 00:00:00

  • Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent.

    abstract::Resistance of malaria parasites has quickly developed to almost all used antimalarial drugs. Accordingly, the discovery of new effective drugs to counter the spread of malaria parasites that are resistant to existing agents, especially acting on multi-targets, is an urgent need. The cysteine protease falcipain-2 (FP-2...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Huang H,Lu W,Li X,Cong X,Ma H,Liu X,Zhang Y,Che P,Ma R,Li H,Shen X,Jiang H,Huang J,Zhu J

    更新日期:2012-01-15 00:00:00

  • Hydroxyl radicals scavenging activity of N-substituted chitosan and quaternized chitosan.

    abstract::N-substituted chitosan and quaternized chitosan were synthesized and their antioxidant activity against hydroxyl radicals was assessed, respectively. Compared with the antioxidant activity of chitosan, the results indicated that the two kinds of chitosan derivatives had different scavenging ability on hydroxyl radical...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Guo Z,Liu H,Chen X,Ji X,Li P

    更新日期:2006-12-15 00:00:00

  • In vitro characterization of the Gd complex of [2,6-pyridinediylbis(methylene nitrilo)] tetraacetic acid (PMN-tetraacetic acid) and of its Eu analogue, suitable bimodal contrast agents for MRI and optical imaging.

    abstract::Gd and Eu complexes of PMN-tetraacetic acid show interesting properties either for MRI or for optical imaging; that is, for the Gd-complex, a high proton relaxivity with favorable water residence time; for the Eu-complex, a luminescence lifetime of 400 micros at room temperature compatible with the use of time-resolve...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Laurent S,Vander Elst L,Wautier M,Galaup C,Muller RN,Picard C

    更新日期:2007-11-15 00:00:00

  • Antimicrobial activity of rationally designed amino terminal modified peptides.

    abstract::Series of short amino terminal modified cationic peptides were designed and synthesized. All of the synthesized compounds were tested against gram-positive as well as gram-negative bacterial strain. Some of the compounds exhibit potent antibacterial activity and no hemolytic activity even at high dose level (1000 micr...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bisht GS,Rawat DS,Kumar A,Kumar R,Pasha S

    更新日期:2007-08-01 00:00:00

  • alpha-Alkyl-alpha-amino-beta-sulphone hydroxamates as potent MMP inhibitors that spare MMP-1.

    abstract::A series of alpha-alkyl-alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-2 and MMP-13, and for selectivity versus MMP-1. Low nanomolar potency was obtained with selectivity versus MMP-1 ranging from >10 to >1000. Selected compounds were orally bioavailable. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Becker DP,DeCrescenzo G,Freskos J,Getman DP,Hockerman SL,Li M,Mehta P,Munie GE,Swearingen C

    更新日期:2001-10-22 00:00:00

  • Pyrrolo[2,3-h]quinolinones: synthesis and photochemotherapic activity.

    abstract::A series of derivatives of the new ring system pyrrolo[2,3-h]quinoline-2-one was synthesized and evaluated as photoreagents toward cultured human tumor cells. Remarkable phototoxycity resulted for some derivatives, especially those bearing the phenyl group at the 7-position. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Barraja P,Diana P,Lauria A,Montalbano A,Almerico AM,Dattolo G,Cirrincione G,Viola G,Dall'Acqua F

    更新日期:2003-08-18 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

  • A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands.

    abstract::A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands is reported. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu KG,Lo JR,Comery TA,Zhang GM,Zhang JY,Kowal DM,Smith DL,Di L,Kerns EH,Schechter LE,Robichaud AJ

    更新日期:2008-07-15 00:00:00

  • Conformationally-restricted cyclic sulfones as potent and selective mTOR kinase inhibitors.

    abstract::Novel conformationally-restricted mTOR kinase inhibitors with cyclic sulfone scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the mTOR potency and selectivity against class I PI3Kα kinase. PF-05139962 was identified with excellent mTOR b...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu KK,Bailey S,Dinh DM,Lam H,Li C,Wells PA,Yin MJ,Zou A

    更新日期:2012-08-01 00:00:00

  • The search for novel TRPV1-antagonists: from carboxamides to benzimidazoles and indazolones.

    abstract::Based on a series of diaryl amides the corresponding inverse amides have been found to be potent TRPV1 receptor antagonists. Benzimidazole and indazolone derivatives prepared retained good potency in vitro and indazolone 4a was identified as a novel TRPV1 receptor antagonist suitable for evaluating orally in animal mo...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fletcher SR,McIver E,Lewis S,Burkamp F,Leech C,Mason G,Boyce S,Morrison D,Richards G,Sutton K,Jones AB

    更新日期:2006-06-01 00:00:00

  • Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy.

    abstract::Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly design...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Plummer MS,Cornicelli J,Roark H,Skalitzky DJ,Stankovic CJ,Bove S,Pandit J,Goodman A,Hicks J,Shahripour A,Beidler D,Lu XK,Sanchez B,Whitehead C,Sarver R,Braden T,Gowan R,Shen XQ,Welch K,Ogden A,Sadagopan N,Baum H

    更新日期:2013-06-01 00:00:00

  • Chlorin e6-cholesterol conjugate and its copper complex. Simple synthesis and entrapping in phospholipid vesicles.

    abstract::Synthesis of 13'[(cholest-5-en)-3beta-yloxyethoxycarbamoyl]-chlorin e6 starting from methylpheophorbide and 3beta(2-hydroxy)-ethoxycholest-5-ene is presented, as well as the preparation of related copper complex. Both conjugates obtained may be simply incorporated in phosphatidyl choline vesicles. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nikolaeva IA,Misharin AY,Ponomarev GV,Timofeev VP,Tkachev YV

    更新日期:2010-05-01 00:00:00

  • Lithospermic acid derivatives from Lithospermum erythrorhizon increased expression of serine palmitoyltransferase in human HaCaT cells.

    abstract::A MeOH extract of the dry root of Lithospermum erythrorhizon showed strong increasing effect on serine palmitoyltransferase (SPT) in normal human keratinocyte cells (HaCaT cells). Bioassay-guided separation on this extract using repeated chromatography resulted in the isolation of lithospermic acid (1) and two derivat...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Thuong PT,Kang KW,Kim JK,Seo DB,Lee SJ,Kim SH,Oh WK

    更新日期:2009-03-15 00:00:00

  • Design and synthesis of bridged piperidine and piperazine isosteres.

    abstract::We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Maertens G,Saavedra OM,Vece V,Reyes MAV,Hocine S,Öney E,Goument B,Mirguet O,Le Tiran A,Gloanec P,Hanessian S

    更新日期:2018-08-15 00:00:00

  • Synthesis of a high-mannose-type glycopeptide analog containing a glucose-asparagine linkage.

    abstract::The title compound was prepared by enzymatic transfer of oligosaccharide to a synthetic pentapeptide containing the Glc-Asn linkage. The compound was not hydrolyzed by glycoamidases from plant and bacterial sources, but it inhibited both enzymes in the micromolar range. Its activity is compared to other potential inhi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Deras IL,Takegawa K,Kondo A,Kato I,Lee YC

    更新日期:1998-07-07 00:00:00

  • From genome to drug lead: identification of a small-molecule inhibitor of the SARS virus.

    abstract::Virtual screening, a fast, computational approach to identify drug leads [Perola, E.; Xu, K.; Kollmeyer, T. M.; Kaufmann, S. H.; Prendergast, F. G. J. Med. Chem.2000, 43, 401; Miller, M. A. Nat. Rev. Drug Disc.2002, 1 220], is limited by a known challenge in crystallographically determining flexible regions of protein...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Dooley AJ,Shindo N,Taggart B,Park JG,Pang YP

    更新日期:2006-02-15 00:00:00

  • RNA aptazyme-tethered large gold nanoparticles for on-the-spot sensing of the aptazyme ligand.

    abstract::A single-step sensing system was developed to visually detect ligands of a cleavase-like RNA aptazyme at room temperature using aptazyme-tethered gold nanoparticles, the electrosteric stability of which was adjusted by increasing their diameter. In this system, the ligand induces self-cleavage of the aptazyme on gold ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ogawa A

    更新日期:2011-01-01 00:00:00

  • Phenylglycine and phenylalanine derivatives as potent and selective HDAC1 inhibitors (SHI-1).

    abstract::An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wilson KJ,Witter DJ,Grimm JB,Siliphaivanh P,Otte KM,Kral AM,Fleming JC,Harsch A,Hamill JE,Cruz JC,Chenard M,Szewczak AA,Middleton RE,Hughes BL,Dahlberg WK,Secrist JP,Miller TA

    更新日期:2008-03-15 00:00:00

  • 2-Substituted 4,5-dihydrothiazole-4-carboxylic acids are novel inhibitors of metallo-β-lactamases.

    abstract::Bacterial resistance to β-lactam antibiotics caused by class B metallo-β-lactamases (MBL), especially for certain hospital-acquired, Gram-negative pathogens, poses a significant threat to public health. We report several 2-substituted 4,5-dihydrothiazole-4-carboxylic acids to be novel MBL inhibitors. Structure activit...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chen P,Horton LB,Mikulski RL,Deng L,Sundriyal S,Palzkill T,Song Y

    更新日期:2012-10-01 00:00:00

  • Hydroxamic acid based histone deacetylase inhibitors with confirmed activity against the malaria parasite.

    abstract::Recent studies have highlighted a key role in regulating gene transcription, in both eukaryotes and prokaryotes, by enzymes that control the acetylation and deacetylation of histones. In particular, inhibitors of histone deacetylases (HDAC-Is) have been shown effective in controlling the development of many parasites,...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Giannini G,Battistuzzi G,Vignola D

    更新日期:2015-02-01 00:00:00

  • Discovery of novel sphingosine kinase-1 inhibitors. Part 2.

    abstract::Building on our initial work, we have identified additional novel inhibitors of sphingosine kinase-1 (SK1). These new analogs address the shortcomings found in our previously reported compounds. Inhibitors 51 and 54 demonstrated oral bioavailability in a rat PK study. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xiang Y,Hirth B,Kane JL Jr,Liao J,Noson KD,Yee C,Asmussen G,Fitzgerald M,Klaus C,Booker M

    更新日期:2010-08-01 00:00:00