CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity.

Abstract:

:DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.

journal_name

Bioorg Med Chem Lett

authors

Pruitt JR,Batt DG,Wacker DA,Bostrom LL,Booker SK,McLaughlin E,Houghton GC,Varnes JG,Christ DD,Covington M,Das AM,Davies P,Graden D,Kariv I,Orlovsky Y,Stowell NC,Vaddi KG,Wadman EA,Welch PK,Yeleswaram S,Solomon KA

doi

10.1016/j.bmcl.2007.03.065

subject

Has Abstract

pub_date

2007-06-01 00:00:00

pages

2992-7

issue

11

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(07)00368-X

journal_volume

17

pub_type

杂志文章
  • Non-peptide alpha(v)beta(3) antagonists: identification of potent, chain-shortened RGD mimetics that incorporate a central pyrrolidinone constraint.

    abstract::Antagonists of the integrin receptor alpha(v)beta(3) are expected to have utility in the treatment of osteoporosis through inhibition of bone resorption. A series of potent, chain-shortened, pyrrolidinone-containing alpha(v)beta(3) receptor antagonists is described. Two sets of diasteromeric pairs of high-affinity ant...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2003.09.055

    authors: Perkins JJ,Duong LT,Fernandez-Metzler C,Hartman GD,Kimmel DB,Leu CT,Lynch JJ,Prueksaritanont T,Rodan GA,Rodan SB,Duggan ME,Meissner RS

    更新日期:2003-12-15 00:00:00

  • Synthesis of novel macrolide derivatives with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains and their antibacterial activity.

    abstract::In an effort to find new antibiotics, a novel series of 14-membered macrolides with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains has been synthesized based on commercially available clarithromycin. Chemical transformation of hydroxy group at position C-3 afforded range of ketolides and acylides. Compared...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.06.023

    authors: Xu P,Liu L,Chen XZ,Li Y,Liu J,Jin ZP,Wang GQ,Lei PS

    更新日期:2009-08-01 00:00:00

  • (11)C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand.

    abstract::Pimavanserin is a selective serotonin 2A receptor (5-HT2AR) inverse agonist that has shown promise for treatment of psychotic symptoms in patients with Parkinson's disease. Here, we detail the (11)C-labeling and subsequently evaluate pimavanserin as a PET-radioligand in pigs. [(11)C]Pimavanserin was obtained by N-meth...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.01.017

    authors: Andersen VL,Hansen HD,Herth MM,Dyssegaard A,Knudsen GM,Kristensen JL

    更新日期:2015-03-01 00:00:00

  • Conjugation of spermine enhances cellular uptake of the stapled peptide-based inhibitors of p53-Mdm2 interaction.

    abstract::We report the first synthesis of the C-terminally spermine-conjugated stapled peptide-based inhibitors of the p53-Mdm2 interaction. Subsequent biological, biophysical and cellular uptake assays with the spermine-conjugated stapled peptides revealed that spermine conjugation minimally affects biological activity while ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.10.009

    authors: Muppidi A,Li X,Chen J,Lin Q

    更新日期:2011-12-15 00:00:00

  • New peptide deformylase inhibitors design, synthesis and pharmacokinetic assessment.

    abstract::The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor's extra hydrophobic binding, providing us a useful tool for searching more efficient PDF inhibitors to fight for horrifying anti...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.05.077

    authors: Lv F,Chen C,Tang Y,Wei J,Zhu T,Hu W

    更新日期:2016-08-01 00:00:00

  • Design, synthesis, and biological evaluation of benzodiazepine-based SUMO-specific protease 1 inhibitors.

    abstract::As the best-characterized ubiquitin-like protein (UBL), small ubiquitin-related modifier (SUMO) was found to conjugate with a number of proteins to regulate cellular functions including transcription, signal transduction, and cell cycle. While E1, E2 and E3 ligases are responsible for the forward SUMOylation reaction,...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.08.101

    authors: Qiao Z,Wang W,Wang L,Wen D,Zhao Y,Wang Q,Meng Q,Chen G,Wu Y,Zhou H

    更新日期:2011-11-01 00:00:00

  • Synthesis and in vitro evaluation of human FP-receptor selective prostaglandin analogues.

    abstract::The in vitro evaluation of a series of saturated prostaglandins revealed that compounds with omega chain aromatic rings retain nanomolar potency for the human prostaglandin F receptor (hFP receptor), exemplified by compound 8. In contrast, the double bonds are required for activity in the series with an acyclic omega ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(00)00273-0

    authors: deLong MA,Amburgey J,Taylor C,Wos JA,Soper DL,Wang Y,Hicks R

    更新日期:2000-07-17 00:00:00

  • Synthesis of enamino-2-oxindoles via conjugate addition between α-azido ketones and 3-alkenyl oxindoles: Cytotoxicity evaluation and apoptosis inducing studies.

    abstract::A facile method for the construction of double bond between 3-ylidene oxindoles and α-azido ketones has been successfully accomplished with a mild base. This method features azido reduction with concomitant double bond formation to provide the new class of bioactive enamino-2-oxindoles. These new compounds were screen...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2018.07.038

    authors: Kumar NP,Vanjari Y,Thatikonda S,Pooladanda V,Sharma P,Sridhar B,Godugu C,Kamal A,Shankaraiah N

    更新日期:2018-12-01 00:00:00

  • Design, synthesis, and anticancer activities of novel perfluoroalkyltriazole-appended 2'-deoxyuridines.

    abstract::We have focused on the C5-modification of 2'-deoxyuridine with substituted heterocycles for bioactivity, such as antiviral or anticancer activity. Herein, we report a novel class of nucleoside analogues with perfluoroalkyltriazole moiety as an anticancer drug candidate. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.07.126

    authors: Park SM,Yang H,Park SK,Kim HM,Kim BH

    更新日期:2010-10-01 00:00:00

  • Diprolyl nitriles as potent dipeptidyl peptidase IV inhibitors.

    abstract::Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.06.043

    authors: Zhao G,Taunk PC,Magnin DR,Simpkins LM,Robl JA,Wang A,Robertson JG,Marcinkeviciene J,Sitkoff DF,Parker RA,Kirby MS,Hamann LG

    更新日期:2005-09-15 00:00:00

  • Efficient microwave-assisted prenylation of pinostrobin and biological evaluation of its derivatives as antitumor agents.

    abstract::Pinostrobin (5-hydroxy-7-methoxyflavanone) obtained in relatively large amounts from fingerroot (Boesenbergia pandurata) was converted to its C-6 and C-8 prenylated derivatives. The Mitsunobu reaction, europium(III)-catalyzed Claisen-Cope rearrangement, and Claisen reaction coupled with cross-metathesis were used as t...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.02.068

    authors: Poerwono H,Sasaki S,Hattori Y,Higashiyama K

    更新日期:2010-04-01 00:00:00

  • Powerful probes for glycosidases: novel, fluorescently tagged glycosidase inhibitors.

    abstract::Amino-1,2,5-trideoxy-2,5-imino-D-mannitol was fluorescently tagged by reaction with dansyl chloride at N-1 or by attachment of a dansyl amide bearing spacer to this centre. Compounds obtained are highly potent inhibitors of beta-glucosidase exhibiting Ki values in the single figure nanomolar range. The 1-N-dansyl subs...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(01)00209-8

    authors: Hermetter A,Scholze H,Stütz AE,Withers SG,Wrodnigg TM

    更新日期:2001-05-21 00:00:00

  • Analogues and derivatives of ciproxifan, a novel prototype for generating potent histamine H3-receptor antagonists.

    abstract::Novel derivatives of the highly potent and selective histamine H3-receptor antagonist ciproxifan (3) with different chain lengths as well as with structural variants of the cyclopropyl ketone moiety have been prepared and screened for their antagonist H3-receptor potencies in vitro and in vivo. Some derivatives (2, 6-...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(00)00473-x

    authors: Stark H,Ligneau X,Sadek B,Ganellin CR,Arrang JM,Schwartz JC,Schunack W

    更新日期:2000-10-16 00:00:00

  • Synthesis and inhibitory activity of 4-alkynyl and 4-alkenylquinazolines: identification of new scaffolds for potent EGFR tyrosine kinase inhibitors.

    abstract::The present study identified several 4-alkynyl and 4-alkenylquinazolines that serve as novel and potent EGFR tyrosine kinase inhibitors. The IC(50) values of these compounds are in the nanomolar range. In addition, the 4-(4-phenylbut-1-yn/en-yl)quinazolines provided scaffolds for potent enzyme inhibition. Chiral discr...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.08.020

    authors: Kitano Y,Suzuki T,Kawahara E,Yamazaki T

    更新日期:2007-11-01 00:00:00

  • Synthesis and antimicrobial activity of some new pyrazole derivatives containing a ferrocene unit.

    abstract::A series of new imines and amines have been synthesized by condensation of 1H-3-ferrocenyl-1-phenylpyrazole-4-carboxaldehyde with the corresponding amines, followed by reduction with sodium borohydride. The synthesized compounds have been screened for their in vitro antimicrobial activity against 11 bacteria and three...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.01.006

    authors: Damljanović I,Vukićević M,Radulović N,Palić R,Ellmerer E,Ratković Z,Joksović MD,Vukićević RD

    更新日期:2009-02-15 00:00:00

  • Sulfenamides as prodrugs of NH-acidic compounds: a new prodrug option for the amide bond.

    abstract::The objective of this report is to introduce the novel concept of utilizing sulfenamides as prodrugs for compounds containing an NH-acidic functionality, particularly weakly acidic amide-type functionalities (amides, ureas, carbamates, etc.). Included are the syntheses and physicochemical characterizations of some mod...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.06.037

    authors: Guarino VR,Karunaratne V,Stella VJ

    更新日期:2007-09-01 00:00:00

  • Inhibition of HIV-1 capsid assembly: optimization of the antiviral potency by site selective modifications at N1, C2 and C16 of a 5-(5-furan-2-yl-pyrazol-1-yl)-1H-benzimidazole scaffold.

    abstract::A uHTS campaign led to the discovery of a 5-(5-furan-2-ylpyrazol-1-yl)-1H-benzimidazole series that inhibits assembly of HIV-1 capsid. Synthetic manipulations at N1, C2 and C16 positions improved the antiviral potency by a . The X-ray structure of 33 complexed with the capsid N-terminal domain allowed identification o...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2012.10.034

    authors: Tremblay M,Bonneau P,Bousquet Y,DeRoy P,Duan J,Duplessis M,Gagnon A,Garneau M,Goudreau N,Guse I,Hucke O,Kawai SH,Lemke CT,Mason SW,Simoneau B,Surprenant S,Titolo S,Yoakim C

    更新日期:2012-12-15 00:00:00

  • Synthesis and biological evaluation of 2-arylimino-3-pyridin-thiazolineone derivatives as antibacterial agents.

    abstract::With an intention to find more potent antibacterial agents, four halogen disubstituted thiazolineone derivatives (2a-d), five halogen monosubstituted thiazolineone derivatives (2e-i), and eleven 2-arylimino-3-pyridin-thiazolineone derivatives (2j-t) were synthesized and screened for their antibacterial activity, bacte...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.03.089

    authors: Cai MG,Wu Y,Chang J

    更新日期:2016-05-15 00:00:00

  • Phenolic P2/P3 core motif as thrombin inhibitors--design, synthesis, and X-ray co-crystal structure.

    abstract::Prototypical thrombin inhibitors were synthesized based on a trisubstituted phenol as a core motif. A naphthylsulfonamide analogue showed excellent antithrombin activity. An X-ray co-crystal structure showed the expected interactions. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.10.082

    authors: Hanessian S,Therrien E,van Otterlo WA,Bayrakdarian M,Nilsson I,Fjellström O,Xue Y

    更新日期:2006-02-15 00:00:00

  • Photoinduced cleavage of DNA by bromofluoroacetophenone-pyrrolecarboxamide conjugates.

    abstract::Bromofluoroacetophenone derivatives which produce fluorine substituted phenyl radicals that cleave DNA upon excitation were investigated as a novel photonuclease. Pyrrolecarboxamide-conjugated bromofluoroacetophenones; 4'-bromo-2'-fluoroacetophenone and 2'-bromo-4'-fluoroacetophenone were synthesized and their DNA cle...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(03)00212-9

    authors: Wender PA,Jeon R

    更新日期:2003-05-19 00:00:00

  • A new dammarane-type saponin from Gynostemma pentaphyllum induces apoptosis in A549 human lung carcinoma cells.

    abstract::Gynostemma pentaphyllum has been widely used as a traditional herb for its antioxidant and immunostimulatory activities. We have previously reported several useful dammarane-type saponins with cytotoxicity against A549 human lung cancer cells from heat-processed G. pentaphyllum. In this study, a new dammarane-type sap...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.02.046

    authors: Xing SF,Jang M,Wang YR,Piao XL

    更新日期:2016-04-01 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

    doi:10.1016/j.bmcl.2020.127727

    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

  • Synthesis and biological activities of NB-506 analogues: Effects of the positions of two hydroxyl groups at the indole rings.

    abstract::In the course of a study of 6-N-amino-substituted analogues of NB-506 (1), a more potent anticancer drug, J-109,404 (2), in which the formyl group of NB-506 was replaced with a 1,3-dihydroxypropane group, was reported. A study of further modification in the positions of two hydroxyl groups at the indole rings of 2 res...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(99)00595-8

    authors: Ohkubo M,Nishimura T,Honma T,Nishimura I,Ito S,Yoshinari T,Suda HA,Morishima H,Nishimura S

    更新日期:1999-12-06 00:00:00

  • Novel small molecule bradykinin B1 receptor antagonists. Part 3: hydroxyurea derivatives.

    abstract::Hydroxy urea moieties are introduced as a new class of bradykinin B(1) receptor antagonists. First, the SAR of the lead compound was systematically explored. Subsequent optimization resulted in the identification of several biaryl-based hydroxyurea bradykinin B(1) receptor antagonists with low-nanomolar activity and v...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.11.121

    authors: Schnatbaum K,Schaudt M,Stragies R,Pfeifer JR,Gibson C,Locardi E,Scharn D,Richter U,Kalkhof H,Dinkel K,Zischinsky G

    更新日期:2010-02-01 00:00:00

  • Inhibitors of HCV NS5B polymerase: synthesis and structure-activity relationships of N-1-heteroalkyl-4-hydroxyquinolon-3-yl-benzothiadiazines.

    abstract::N-1-Alkylamino and N-1-alkyloxy-4-hydroxyquinolon-3-yl benzothiadiazines were synthesized and evaluated as inhibitors of genotype 1 HCV polymerase. The N-1-alkyloxy derivatives were not potent inhibitors, however N-1-alkylamino derivatives displayed comparable potency to carbon analogs. Analogs with aliphatic substitu...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2005.01.071

    authors: Pratt JK,Donner P,McDaniel KF,Maring CJ,Kati WM,Mo H,Middleton T,Liu Y,Ng T,Xie Q,Zhang R,Montgomery D,Molla A,Kempf DJ,Kohlbrenner W

    更新日期:2005-03-15 00:00:00

  • Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist (MABA) dual pharmacology molecules.

    abstract::We sought to design dual pharmacology bronchodilators targeting both the M(3) muscarinic acetylcholine and beta-2 adrenergic (β(2)) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptor...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.01.043

    authors: Hughes AD,Chin KH,Dunham SL,Jasper JR,King KE,Lee TW,Mammen M,Martin J,Steinfeld T

    更新日期:2011-03-01 00:00:00

  • Biological properties of synthetic glycoconjugate mimics of heparin comprising different molecular spacers.

    abstract::The in vitro antithrombotic activity of synthetic glycoconjugates I and II, comprising a flexible polyethylene glycol type and a rigid polyglucose type spacer, respectively, are compared to heparin. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(98)00382-5

    authors: Dreef-Tromp CM,Basten JE,Broekhoven MA,van Dinther TG,Petitou M,van Boeckel CA

    更新日期:1998-08-18 00:00:00

  • Protein ligand-tethered synthetic calcium indicator for localization control and spatiotemporal calcium imaging in plant cells.

    abstract::In plant biology, calcium ions are involved in a variety of intriguing biological phenomena as a secondary messenger. However, most conventional calcium indicators are not applicable for plant cells because of the difficulty with their localization control in plant cells. We here introduce a method to monitor spatiote...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.11.055

    authors: Takaoka Y,Shigenaga M,Imai M,Nukadzuka Y,Ishimaru Y,Saito K,Yokoyama R,Nishitani K,Ueda M

    更新日期:2016-01-01 00:00:00

  • Synthesis and activity of novel tetrazole compounds and their pyrazole-4-carbonitrile precursors against Leishmania spp.

    abstract::A new series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a-m) and their precursor 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a-m) were synthesized and evaluated as antileishmanials against Leishmania braziliensis and Leishmania amazonensis promastigotes in vitro. In parallel, the cytotoxicity ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2013.09.062

    authors: Faria JV,dos Santos MS,Bernardino AM,Becker KM,Machado GM,Rodrigues RF,Canto-Cavalheiro MM,Leon LL

    更新日期:2013-12-01 00:00:00

  • New pyrrole derivatives as antimycobacterial agents analogs of BM212.

    abstract::During the course of our investigations in the field of azole antimicrobial agents, we have identified BM212 a pyrrole derivative with good in vitro activity against mycobacteria and candidae. These findings prompted us to prepare new pyrrole derivatives 2-6 in the hope of increasing the activity. The microbiological ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(99)00510-7

    authors: Biava M,Fioravanti R,Porretta GC,Deidda D,Maullu C,Pompei R

    更新日期:1999-10-18 00:00:00