共查询到20条相似文献,搜索用时 31 毫秒
1.
Dhanak D Christmann LT Darcy MG Jurewicz AJ Keenan RM Lee J Sarau HM Widdowson KL White JR 《Bioorganic & medicinal chemistry letters》2001,11(11):1441-1444
The discovery of a series of phenylalanine derived CCR3 antagonists is reported. Parallel, solution-phase library synthesis has been utilized to delineate the structure-activity relationship leading to the synthesis of highly potent, CCR3-selective antagonists. 相似文献
2.
RJ Cherney R Mo DT Meyer AD Pechulis MA Guaciaro YC Lo G Yang PB Miller PA Scherle Q Zhao ME Cvijic JC Barrish CP Decicco PH Carter 《Bioorganic & medicinal chemistry letters》2012,22(19):6181-6184
We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide. 相似文献
3.
Sato I Morihira K Inami H Kubota H Morokata T Suzuki K Hamada N Iura Y Nitta A Imaoka T Takahashi T Takeuchi M Ohta M Tsukamoto S 《Bioorganic & medicinal chemistry》2008,16(1):144-156
A novel class of potent CCR3 receptor antagonists were designed and synthesized starting from N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide (1),which was found by subjecting our chemical library to high throughput screening (HTS). The CCR3 inhibitory activity of the synthesized compounds against eotaxin-induced Ca(2+) influx was evaluated using CCR3-expressing preB cells. Systematic chemical modifications of 1 revealed that the 6-fluoro-2-naphthylmethyl moiety was essential for CCR3 inhibitory activity in this new series of CCR3 antagonists. Further structural modifications of the benzamide and piperidine moieties of 1 led to the identification of exo-N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide [corrected] (31) as a potent CCR3 antagonist with an IC(50) value of 0.020 microM. 相似文献
4.
Mark Furber Lilian Alcaraz Christopher Luckhurst Ash Bahl Haydn Beaton Keith Bowers John Collington Rebecca Denton David Donald Elizabeth Kinchin Cathy MacDonald Aaron Rigby Rob Riley Matt Soars Brian Springthorpe Peter Webborn 《Bioorganic & medicinal chemistry letters》2012,22(24):7702-7706
The discovery of potent small molecule dual antagonists of the human CCR3 and H1 receptors is described for the treatment of allergic diseases, for example, asthma and allergic rhinitis. Optimizing in vitro potency and metabolic stability, starting from a CCR1 lead compound, led to compound 20 with potent dual CCR3/H1 activity and in vitro metabolic stability. 相似文献
5.
6.
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 Newton RC Decicco CP Carter PH Ko SS 《Bioorganic & medicinal chemistry letters》2007,17(11):2992-2997
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. 相似文献
7.
Imamura S Nishikawa Y Ichikawa T Hattori T Matsushita Y Hashiguchi S Kanzaki N Iizawa Y Baba M Sugihara Y 《Bioorganic & medicinal chemistry》2005,13(2):397-416
Replacement of the 5-oxopyrrolidin-3-yl fragment in the previously reported lead structure with a 1-acetylpiperidin-4-yl group led to the discovery of a novel series of potent CCR5 antagonists. Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists. The selected compound 11f showed excellent antiviral activity against CCR5-using HIV-1 replication in human peripheral blood mononuclear cells (EC50=0.59 nM) and an acceptable pharmacokinetic profile in dogs. 相似文献
8.
Gong L Hogg JH Collier J Wilhelm RS Soderberg C 《Bioorganic & medicinal chemistry letters》2003,13(20):3597-3600
As part of our investigation into the development of potent CCR3 antagonists, a series of piperidine analogues was designed and prepared. Exploration of the piperidine core examined both the basicity and the location of a nitrogen, as well as conformational variants. The bicyclo-piperidine 24c was found to be the most potent inhibitor of CCR3 with an IC(50) of 0.0082 microM in the binding assay and 0.0024 microM in the chemotaxis assay. 相似文献
9.
Sk Abdul Amin Nilanjan Adhikari Sandip Kumar Baidya Shovanlal Gayen 《Journal of biomolecular structure & dynamics》2019,37(1):75-94
Chemokines trigger numerous inflammatory responses and modulate the immune system. The interaction between monocyte chemoattractant protein-1 and chemokine receptor 2 (CCR2) may be the cause of atherosclerosis, obesity, and insulin resistance. However, CCR2 is also implicated in other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, asthma, and neuropathic pain. Therefore, there is a paramount importance of designing potent and selective CCR2 antagonists despite a number of drug candidates failed in clinical trials. In this article, 83 CCR2 antagonists by Jhonson and Jhonson Pharmaceuticals have been considered for robust validated multi-QSAR modeling studies to get an idea about the structural and pharmacophoric requirements for designing more potent CCR2 antagonists. All these QSAR models were validated and statistically reliable. Observations resulted from different modeling studies correlated and validated results of other ones. Finally, depending on these QSAR observations, some new molecules were proposed that may exhibit higher activity against CCR2. 相似文献
10.
Shankaran K Donnelly KL Shah SK Guthikonda RN MacCoss M Mills SG Gould SL Malkowitz L Siciliano SJ Springer MS Carella A Carver G Hazuda D Holmes K Kessler J Lineberger J Miller MD Emini EA Schleif WA 《Bioorganic & medicinal chemistry letters》2004,14(13):3419-3424
Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2014,24(4):1239-1242
SAR study of 5-aminooctahydrocyclopentapyrrole-3a-carboxamide scaffold led to identification of several CCR2 antagonists with potent activity in both binding and functional assays. Their cardiovascular safety and pharmacokinetic properties were also evaluated. 相似文献
12.
Batt DG Houghton GC Roderick J Santella JB Wacker DA Welch PK Orlovsky YI Wadman EA Trzaskos JM Davies P Decicco CP Carter PH 《Bioorganic & medicinal chemistry letters》2005,15(3):787-791
The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils. 相似文献
13.
Mirzadegan T Diehl F Ebi B Bhakta S Polsky I McCarley D Mulkins M Weatherhead GS Lapierre JM Dankwardt J Morgans D Wilhelm R Jarnagin K 《The Journal of biological chemistry》2000,275(33):25562-25571
Monocyte chemoattracant-1 (MCP-1) stimulates leukocyte chemotaxis to inflammatory sites, such as rheumatoid arthritis, atherosclerosis, and asthma, by use of the MCP-1 receptor, CCR2, a member of the G-protein-coupled seven-transmembrane receptor superfamily. These studies identified a family of antagonists, spiropiperidines. One of the more potent compounds blocks MCP-1 binding to CCR2 with a K(d) of 60 nm, but it is unable to block binding to CXCR1, CCR1, or CCR3. These compounds were effective inhibitors of chemotaxis toward MCP-1 but were very poor inhibitors of CCR1-mediated chemotaxis. The compounds are effective blockers of MCP-1-driven inhibition of adenylate cyclase and MCP-1- and MCP-3-driven cytosolic calcium influx; the compounds are not agonists for these pathways. We showed that glutamate 291 (Glu(291)) of CCR2 is a critical residue for high affinity binding and that this residue contributes little to MCP-1 binding to CCR2. The basic nitrogen present in the spiropiperidine compounds may be the interaction partner for Glu(291), because the basicity of this nitrogen was essential for affinity; furthermore, a different class of antagonists, a class that does not have a basic nitrogen (2-carboxypyrroles), were not affected by mutations of Glu(291). In addition to the CCR2 receptor, spiropiperidine compounds have affinity for several biogenic amine receptors. Receptor models indicate that the acidic residue, Glu(291), from transmembrane-7 of CCR2 is in a position similar to the acidic residue contributed from transmembrane-3 of biogenic amine receptors, which may account for the shared affinity of spiropiperidines for these two receptor classes. The models suggest that the acid-base pair, Glu(291) to piperidine nitrogen, anchors the spiropiperidine compound within the transmembrane ovoid bundle. This binding site may overlap with the space required by MCP-1 during binding and signaling; thus the small molecule ligands act as antagonists. An acidic residue in transmembrane region 7 is found in most chemokine receptors and is rare in other serpentine receptors. The model of the binding site may suggest ways to make new small molecule chemokine receptor antagonists, and it may rationalize the design of more potent and selective antagonists. 相似文献
14.
Zhang X Hufnagel H Markotan T Lanter J Cai C Hou C Singer M Opas E McKenney S Crysler C Johnson D Sui Z 《Bioorganic & medicinal chemistry letters》2011,21(18):5577-5582
A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG. 相似文献
15.
Finke PE Oates B Mills SG MacCoss M Malkowitz L Springer MS Gould SL DeMartino JA Carella A Carver G Holmes K Danzeisen R Hazuda D Kessler J Lineberger J Miller M Schleif WA Emini EA 《Bioorganic & medicinal chemistry letters》2001,11(18):2475-2479
(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50=10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists. 相似文献
16.
Simon Peace Joanne Philp Carl Brooks Val Piercy Kitty Moores Chris Smethurst Steve Watson Simon Gaines Mara Zippoli Claudette Mookherjee Robert Ife 《Bioorganic & medicinal chemistry letters》2010,20(13):3961-3964
A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pKa, yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma. 相似文献
17.
Pasternak A Goble SD Doss GA Tsou NN Butora G Vicario PP Ayala JM Struthers M Demartino JA Mills SG Yang L 《Bioorganic & medicinal chemistry letters》2008,18(4):1374-1377
In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold. 相似文献
18.
Dooseop Kim Liping Wang Charles G. Caldwell Ping Chen Paul E. Finke Bryan Oates Malcolm MacCoss Sander G. Mills Lorraine Malkowitz Sandra L. Gould Julie A. DeMartino Martin S. Springer Daria Hazuda Michael Miller Joseph Kessler Renee Danzeisen Gwen Carver Anthony Carella Karen Holmes Janet Lineberger William A. Schleif Emilio A. Emini 《Bioorganic & medicinal chemistry letters》2001,11(24):3099-3102
A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(7):1843-1845
We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment. 相似文献
20.
Naya A Kobayashi K Ishikawa M Ohwaki K Saeki T Noguchi K Ohtake N 《Bioorganic & medicinal chemistry letters》2001,11(9):1219-1223
In searching for a novel CCR3 receptor antagonist, we designed a library that included a variety of carboxamide derivatives based on the structure of our potent antagonists for human CCR1 and CCR3 receptors, and screened the new compounds for inhibitory activity against 125I-Eotaxin binding to human CCR3 receptors expressed in CHO cells. Among them, two 2-(benzothiazolethio)acetamide derivatives (1a and 2a) showed binding affinities with IC50 values of 750 and 1000 nM, respectively, for human CCR3 receptors. These compounds (1a and 2a) also possessed weak binding affinities for human CCR1 receptors. We selected la as a lead compound for derivatization to improve in vitro potency and selectivity for CCR3 over CCRI receptors. Derivatization of la by incorporating substituents into each benzene ring of the benzothiazole and piperidine side chain resulted in the discovery of a compound (1b) exhibiting 820-fold selectivity for CCR3 receptors (IC50 = 2.3 nM) over CCR1 receptors (IC50 = 1900 nM). This compound (1b) also showed potent functional antagonist activity for inhibiting Eotaxin (IC50 = 27 nM)- or RANTES (IC50 = 13 nM)-induced Ca2+ increases in eosinophils. 相似文献