1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors: separation of desired cellular activity from undesired tissue accumulation through optimization of basic nitrogen pka.

Abstract:

:Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pk(a) of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pk(a) 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.

journal_name

Bioorg Med Chem Lett

authors

Arbuckle W,Baugh M,Belshaw S,Bennett DJ,Bruin J,Cai J,Cameron KS,Claxton C,Dempster M,Everett K,Fradera X,Hamilton W,Jones PS,Kinghorn E,Long C,Martin I,Robinson J,Westwood P

doi

10.1016/j.bmcl.2010.12.065

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

932-5

issue

3

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(10)01829-9

journal_volume

21

pub_type

杂志文章
  • Schiff's bases of quinazolinone derivatives: Synthesis and SAR studies of a novel series of potential anti-inflammatory and antioxidants.

    abstract::A series of quinazolinone derived Schiff base derivatives 7-28 were synthesized and characterized as novel antioxidants and anti-inflammatory agents. The in vitro antioxidant activities of these compounds were evaluated and compared with commercial antioxidants ascorbic acid (AA), gallic acid (GA), butylatedhydroxytol...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章,评审

    doi:10.1016/j.bmcl.2015.01.010

    authors: Rakesh KP,Manukumar HM,Gowda DC

    更新日期:2015-03-01 00:00:00

  • The mechanism of the irreversible inhibition of estrone sulfatase (ES) through the consideration of a range of methane- and amino-sulfonate-based compounds.

    abstract::We report the results of our study into a series of simple phenyl and alkyl sulfamates and alkyl methanesulfonates as potential inhibitors of the enzyme estrone sulfatase (ES). The results of the study show that the substituted phenyl sulfamates are good irreversible inhibitors; the alkyl sulfamate compounds were foun...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(02)00137-3

    authors: Ahmed S,James K,Owen CP,Patel CK,Sampson L

    更新日期:2002-05-06 00:00:00

  • Vialinin A and thelephantin G, potent inhibitors of tumor necrosis factor-α production, inhibit sentrin/SUMO-specific protease 1 enzymatic activity.

    abstract::Several p-terphenyl compounds have been isolated from the edible Chinese mushroom Thelephora vialis. Vialinin A, a p-terphenyl compound, strongly inhibits tumor necrosis factor-α production and release. Vialinin A inhibits the enzymatic activity of ubiquitin-specific peptidase 5, one of the target molecules in RBL-2H3...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.07.051

    authors: Yoshioka Y,Namiki D,Makiuchi M,Sugaya K,Onose J,Ashida H,Abe N

    更新日期:2016-09-01 00:00:00

  • Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors.

    abstract::Guided by structure-based design, we synthesized two novel series of potent inhibitors of BACE1 and generated extensive SAR around both the prime and non-prime side binding pockets. The key feature of both series is a cyclic amine motif specifically crafted to achieve interactions with both the flap and with the S2' p...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2008.04.050

    authors: Cumming JN,Le TX,Babu S,Carroll C,Chen X,Favreau L,Gaspari P,Guo T,Hobbs DW,Huang Y,Iserloh U,Kennedy ME,Kuvelkar R,Li G,Lowrie J,McHugh NA,Ozgur L,Pan J,Parker EM,Saionz K,Stamford AW,Strickland C,Tadesse D,

    更新日期:2008-06-01 00:00:00

  • Discovery, synthesis, and structure-activity studies of tetrazole based growth hormone secretagogues.

    abstract::A novel class of Growth Hormone Secretagogues (GHS), based on a tetrazole template, has been discovered. In vitro SAR and in vivo potency within this new class of GHS are described. The tetrazole 9q exhibits good oral bioavailability in rats and dogs as well as efficacy following an oral 10 mg/kg dose in dogs. Solutio...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.07.099

    authors: Hernández AS,Cheng PT,Musial CM,Swartz SG,George RJ,Grover G,Slusarchyk D,Seethala RK,Smith M,Dickinson K,Giupponi L,Longhi DA,Flynn N,Murphy BJ,Gordon DA,Biller SA,Robl JA,Tino JA

    更新日期:2007-11-01 00:00:00

  • Synthesis, structure and in vitro cytostatic activity of ferrocene-Cinchona hybrids.

    abstract::Exploring copper(I)- and ruthenium(II)-catalyzed azide-alkyne cycloadditions and a Sonogashira protocol, novel cytostatic ferrocene-cinchona hybrids were synthetized displaying significant in vitro activity on HepG-2 and HT-29 cells. Preliminary SAR studies disclosed that compounds incorporating linkers with 1,2,3-tri...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.12.059

    authors: Kocsis L,Szabó I,Bősze S,Jernei T,Hudecz F,Csámpai A

    更新日期:2016-02-01 00:00:00

  • Synthesis and inhibitory activity of ubiquinone-acetogenin hybrid inhibitor with bovine mitochondrial complex I.

    abstract::To elucidate the inhibitory action of acetogenins, the most potent inhibitors of mitochondrial complex I, we synthesized an acetogenin analogue which possesses a ubiquinone ring (i.e., the physiological substrate of complex I) in place of the alpha,beta-unsaturated gamma-lactone ring of natural acetogenins, and named ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(03)00439-6

    authors: Yabunaka H,Abe M,Kenmochi A,Hamada T,Nishioka T,Miyoshi H

    更新日期:2003-07-21 00:00:00

  • Effect of structural modification on the inhibitory selectivity of rutaecarpine derivatives on human CYP1A1, CYP1A2, and CYP1B1.

    abstract::Derivatives of a CYP1A2 inhibitor rutaecarpine were synthesized to have potent and selective inhibition of human CYP1 members. Structural modelling shows a good fitting of rutaecarpine with the putative active site of human CYP1A2. Among the derivatives, 10- and 11-methoxyrutaecarpine are the most selective CYP1B1 inh...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(03)00469-4

    authors: Don MJ,Lewis DF,Wang SY,Tsai MW,Ueng YF

    更新日期:2003-08-04 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

    doi:10.1016/j.bmcl.2010.03.109

    authors: Watts JK,Corey DR

    更新日期:2010-06-01 00:00:00

  • Resveratrol as a new type of DNA-cleaving agent.

    abstract::The first demonstration of DNA cleavage by resveratrol '3,5,4'-trihydroxy-trans-stilbene' is presented. Resveratrol mediated relaxation of pBR322 at micromolar concentrations in the presence of Cu2+. Evidence is provided that resveratrol is capable of binding to DNA, and that the Cu(2+)-dependent DNA damage is more li...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(98)00585-x

    authors: Fukuhara K,Miyata N

    更新日期:1998-11-17 00:00:00

  • Identification and optimization of novel partial agonists of neuromedin B receptor using parallel synthesis.

    abstract::The design and parallel synthesis of potent, small molecule partial agonists of Neuromedin B receptor based on the 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide core is described. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.04.045

    authors: Shuttleworth SJ,Lizarzaburu ME,Chai A,Coward P

    更新日期:2004-06-21 00:00:00

  • A novel arylethynyltriazole acyclonucleoside inhibits proliferation of drug-resistant pancreatic cancer cells.

    abstract::Novel arylethynyltriazole acyclonucleosides were synthesized and assessed for their anticancer activity on drug-resistant pancreatic cancer MiaPaCa-2 cells. One lead compound was found to have much more potent apoptosis-related antiproliferative effects than gemcitabine, the current first-line treatment for pancreatic...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.08.093

    authors: Wang M,Xia Y,Fan Y,Rocchi P,Qu F,Iovanna JL,Peng L

    更新日期:2010-10-15 00:00:00

  • Synthesis and biological evaluation of L-cysteine derivatives as mitotic kinesin Eg5 inhibitors.

    abstract::Inhibition of Eg5 represents a novel approach for the treatment of cancer. Here, we report the synthesis and structure-activity relationship of S-trityl-L-cysteine (STLC) derivatives as Eg5 inhibitors. Some of these derivatives such as 4f demonstrated enhanced inhibitory activity against Eg5 and induced mitotic arrest...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.04.101

    authors: Ogo N,Oishi S,Matsuno K,Sawada J,Fujii N,Asai A

    更新日期:2007-07-15 00:00:00

  • Anti-tubercular agents. Part IV: Synthesis and antimycobacterial evaluation of nitroheterocyclic-based 1,2,4-benzothiadiazines.

    abstract::In continuation of our earlier work on benzothiadiazines, we have prepared a series of nitrofuran, nitrothiophene and arylfuran coupled benzothiadiazines and evaluated them for antimycobacterial and antibacterial activities. One of the compounds 2f has shown good in vitro antimycobacterial activity. All the synthesize...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.07.027

    authors: Kamal A,Ahmed SK,Reddy KS,Khan MN,Shetty RV,Siddhardha B,Murthy US,Khan IA,Kumar M,Sharma S,Ram AB

    更新日期:2007-10-01 00:00:00

  • Identification of 2,3,6-trisubstituted quinoxaline derivatives as a Wnt2/β-catenin pathway inhibitor in non-small-cell lung cancer cell lines.

    abstract::We screened 1434 small heterocyclic molecules and identified thirteen 2,3,6-trisubstituted quinoxaline derivatives that were able to inhibit the Wnt/β-catenin signal pathway and cell proliferation. In the screen, some of the hit compounds such as the ethylene group-coupled quinoxaline derivatives were shown to hold pr...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.07.088

    authors: Lee SB,Park YI,Dong MS,Gong YD

    更新日期:2010-10-01 00:00:00

  • Isolation and structure of SCH 351633: a novel hepatitis C virus (HCV) NS3 protease inhibitor from the fungus Penicillium griseofulvum.

    abstract::A new hepatitis C virus (HCV) protease inhibitor designated as Sch 351633 (1) was isolated from the fungus, Penicillium griseofulvum. Structure elucidation of 1 was accomplished by analysis of spectroscopic data, which determined compound 1 to be a bicyclic hemiketal lactone. Compound 1 exhibited inhibitory activity i...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(99)00321-2

    authors: Chu M,Mierzwa R,He L,King A,Patel M,Pichardo J,Hart A,Butkiewicz N,Puar MS

    更新日期:1999-07-19 00:00:00

  • Hydrolysis of linear DNA duplex catalyzed by Co(III) complex of cyclen attached to polystyrene.

    abstract::To design artificial restriction enzymes, synthetic catalytic centers that effectively hydrolyze linear double-stranded polydeoxyribonucleotides are needed. The Co(III) complex of cyclen (CoCyc) attached to polystyrene derivatives hydrolyzes linearized pUC18 DNA with half-lives as short as 30 min at 25 degrees C. The ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(01)00615-1

    authors: Jeung CS,Song JB,Kim YH,Suh J

    更新日期:2001-12-03 00:00:00

  • 5-Aminomethylquinoxaline-2,3-diones. Part I: A novel class of AMPA receptor antagonists.

    abstract::A series of 5-aminomethylquinoxaline-2,3-diones have been identified as potent and selective AMPA antagonists. Some of these compounds are also active at the glycine-binding site of the NMDA receptors. A number of these novel, water-soluble quinoxaline-2,3-dione derivatives display protective effects in the electrosho...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(97)10186-x

    authors: Auberson YP,Bischoff S,Moretti R,Schmutz M,Veenstra SJ

    更新日期:1998-01-06 00:00:00

  • Folate pro-drug of cystamine as an enhanced treatment for nephropathic cystinosis.

    abstract::Nephropathic cystinosis is a rare autosomal recessive disease characterised by raised intracellular levels of the amino acid, cystine. If untreated, the disease, progressively deteriorates towards end stage renal disease (ESRD) at the end of the first decade. The disease is caused by a defect in the lysosomal transpor...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.02.048

    authors: Omran Z,Kay G,Hector EE,Knott RM,Cairns D

    更新日期:2011-04-15 00:00:00

  • Novel malonamide derivatives as potent kappa opioid receptor agonists.

    abstract::A novel series of malonamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.01.053

    authors: Chu GH,Gu M,Cassel JA,Belanger S,Graczyk TM,DeHaven RN,Conway-James N,Koblish M,Little PJ,DeHaven-Hudkins DL,Dolle RE

    更新日期:2007-04-01 00:00:00

  • Small-molecule microarrays: development of novel linkers and an efficient detection method for bound proteins.

    abstract::Novel isocyanate and diazoketone linkers possessing polyoxypropylenediamine as a spacer for small-molecule microrray are developed. White light interferometry is introduced to detect bound proteins on the glass slides without using chemically modified proteins. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2006.04.057

    authors: Kurosu M,Mowers WA

    更新日期:2006-07-01 00:00:00

  • Synthesis of C-5a-chain extended derivatives of 4-epi-isofagomine: Powerful β-galactosidase inhibitors and low concentration activators of GM1-gangliosidosis-related human lysosomal β-galactosidase.

    abstract::From an easily available partially protected formal derivative of 1-deoxymannojirimycin, by hydroxymethyl chain-branching and further elaboration, lipophilic analogs of the powerful β-d-galactosidase inhibitor 4-epi-isofagomine have become available. New compounds exhibit improved inhibitory activities comparable to b...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.01.059

    authors: Thonhofer M,Weber P,Santana AG,Fischer R,Pabst BM,Paschke E,Schalli M,Stütz AE,Tschernutter M,Windischhofer W,Withers SG

    更新日期:2016-03-01 00:00:00

  • Hydroxyl substituted benzoic acid/cinnamic acid derivatives: Tyrosinase inhibitory kinetics, anti-melanogenic activity and molecular docking studies.

    abstract::The inhibition of tyrosinase is an established strategy for treating hyperpigmentation. Our previous findings demonstrated that cinnamic acid and benzoic acid scaffolds can be effective tyrosinase inhibitors with low toxicity. The hydroxyl substituted benzoic and cinnamic acid moieties of these precursors were incorpo...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2019.126722

    authors: Nazir Y,Saeed A,Rafiq M,Afzal S,Ali A,Latif M,Zuegg J,Hussein WM,Fercher C,Barnard RT,Cooper MA,Blaskovich MAT,Ashraf Z,Ziora ZM

    更新日期:2020-01-01 00:00:00

  • Enhanced pneumocystis carinii activity of new primaquine analogues.

    abstract::New analogues of the venerable antimalarial drug primaquine have been synthesized and bioassayed in vivo against Pneumocystis carinii, a life-threatening infection common among immunosuppressed patients. Two of these new compounds are significantly more active than primaquine itself, and provide new information for fu...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(00)00436-4

    authors: Goodwin TE,Boylan CJ,Current WL,Byrd JC,Edwards CB,Fuller DA,Green JL,Larocca CD,Raney KD,Ross AS,Tucker WA

    更新日期:2000-10-02 00:00:00

  • α-Methylated simplified resiniferatoxin (sRTX) thiourea analogues as potent and stereospecific TRPV1 antagonists.

    abstract::A series of α-methylated analogues of the potent sRTX thiourea antagonists were investigated as rTRPV1 ligands in order to examine the effect of α-methylation on receptor activity. The SAR analysis indicated that activity was stereospecific with the (R)-configuration of the newly formed chiral center providing high bi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2014.04.054

    authors: Kim HS,Jin MK,Kang SU,Lim JO,Tran PT,Hoang VH,Ann J,Ha TH,Pearce LV,Pavlyukovets VA,Blumberg PM,Lee J

    更新日期:2014-06-15 00:00:00

  • Role of the phenolic hydroxyl group in the biological activities of simplified analogue of aplysiatoxin with antiproliferative activity.

    abstract::The 18-deoxy derivative (3) of a simplified analogue (1) of aplysiatoxin with antiproliferative activity was synthesized to examine the role of the phenolic hydroxyl group at position 18 in the biological activities of 1. Compound 3 as well as 1 showed significant affinity for protein kinase Cδ (PKCδ), and the antipro...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.08.051

    authors: Yanagita RC,Kamachi H,Tanaka K,Murakami A,Nakagawa Y,Tokuda H,Nagai H,Irie K

    更新日期:2010-10-15 00:00:00

  • Synthesis and biological evaluation of [D-lysine]8cyclosporin A analogs as potential anti-HCV agents.

    abstract::An efficient synthesis of [D-lysine](8)cyclosporin A has been developed. Several analogs of [D-lysine](8)cyclosporin A have been synthesized and show promising anti-HCV activity, particularly compounds 39 and 43, which each exhibit an anti-HCV EC(50)<200 nM, and are each ≥50-fold less immunosuppressive than cyclospori...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.09.036

    authors: Scribner A,Houck D,Huang Z,Mosier S,Peel M,Scorneaux B

    更新日期:2010-11-15 00:00:00

  • 1-[4-(1H-Benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea derivatives as small molecule heparanase inhibitors.

    abstract::A novel class of 1-[4-(1H-benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-ureas are described as potent inhibitors of heparanase. Among them are 1,3-bis-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea (7a) and 1,3-bis-[4-(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl]-urea (7d), which displayed good heparanase i...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.09.069

    authors: Pan W,Miao HQ,Xu YJ,Navarro EC,Tonra JR,Corcoran E,Lahiji A,Kussie P,Kiselyov AS,Wong WC,Liu H

    更新日期:2006-01-15 00:00:00

  • Further constituents of Galianthe thalictroides (Rubiaceae) and inhibition of DNA topoisomerases I and IIα by its cytotoxic β-carboline alkaloids.

    abstract::A new cytotoxic β-carboline alkaloid, 1-methyl-3-(2-hydroxypropan-2-yl)-2-(5-methoxy-9H-β-carbolin-1-yl)-cyclopentanol (1), was isolated from roots of Galianthe thalictroides, together with the alkaloid 1-(hydroxymethyl)-3-(2-hydroxypropan-2-yl)-2-(5-methoxy-9H-β-carbolin-1-yl)-cyclopentanol (2), the anthraquinones 1-...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2014.01.039

    authors: de Oliveira Figueiredo P,Perdomo RT,Garcez FR,de Fatima Cepa Matos M,de Carvalho JE,Garcez WS

    更新日期:2014-03-01 00:00:00

  • New merosesquiterpenes from a Vietnamese marine sponge of Spongia sp. and their biological activities.

    abstract::The investigation of the Vietnamese marine sponge Spongia sp. led to the isolation of three new sesquiterpene phenols, langconols A-C (1-3), and one new sesquiterpene hydroxyquinone, langcoquinone C (4), together with two known meroterpenoids (5 and 6). Their structures were determined on the basis of spectroscopic an...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2017.05.060

    authors: Nguyen HM,Ito T,Kurimoto SI,Ogawa M,Win NN,Hung VQ,Nguyen HT,Kubota T,Kobayashi J,Morita H

    更新日期:2017-07-15 00:00:00