共查询到20条相似文献,搜索用时 8 毫秒
1.
Jutta Wanner Lijing Chen Rémy C. Lemoine Rama Kondru Andreas Jekle Gabrielle Heilek André deRosier Changhua Ji Pamela W. Berry David M. Rotstein 《Bioorganic & medicinal chemistry letters》2010,20(22):6802-6807
Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists led to the discovery of compounds with increased intrinsic permeability. This effort led to the identification of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2014,24(7):1681-1684
Novel potent and selective mineralocorticoid receptor antagonists were identified, utilizing heterocyclic amide replacements in the oxazolidinedione series. Structure–activity relationship (SAR) efforts focused on improving lipophilic ligand efficiency (LLE) while maintaining nuclear hormone receptor selectivity and reasonable pharmacokinetic profiles. 相似文献
3.
Rémy C. Lemoine Ann C. Petersen Lina Setti Lijing Chen Jutta Wanner Andreas Jekle Gabrielle Heilek André deRosier Changhua Ji David M. Rotstein 《Bioorganic & medicinal chemistry letters》2010,20(6):1830-1833
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the conformationally restricted 4-aminopiperidine ring found in several series of CCR5 antagonists. 相似文献
4.
Duan M Kazmierski WM Tallant M Jun JH Edelstein M Ferris R Todd D Wheelan P Xiong Z 《Bioorganic & medicinal chemistry letters》2011,21(21):6381-6385
A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in 1. This class of CCR5 compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays. Further evaluation of these compounds indicated that 16-R not only substantially enhanced its stability, but also exhibited excellent pharmacokinetics properties. 相似文献
5.
Luo G Mattson GK Bruce MA Wong H Murphy BJ Longhi D Antal-Zimanyi I Poindexter GS 《Bioorganic & medicinal chemistry letters》2004,14(24):1721-5978
4-Amino-N-arylpiperidines serve as effective bioisosteres for N-arylpiperazines in the series of dihydropyridine NPY1 receptor antagonists. These were prepared by a ZnCl2-mediated reductive amination reaction between elaborated primary amines, 2 or 5, and 4-arylpiperidones. 相似文献
6.
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
7.
Seto M Miyamoto N Aikawa K Aramaki Y Kanzaki N Iizawa Y Baba M Shiraishi M 《Bioorganic & medicinal chemistry》2005,13(2):363-386
In order to develop orally active CCR5 antagonists, 1-propyl- or 1-isobutyl-1-benzazepine derivatives containing a sulfoxide moiety have been designed, synthesized, and evaluated for their biological activities. Sulfoxide compounds containing a 2-pyridyl group were first investigated, which led to discovering that the presence of a methylene group between the sulfoxide moiety and 2-pyridyl group was necessary for increased inhibitory activity in a binding assay. After further chemical modification, it was found that replacement of the pyridyl group with an imidazolyl or 1,2,4-triazolyl group enhanced activity in the binding assay and that S-sulfoxide compounds were more active than R-isomers. Particularly, compounds (S)-4r, (S)-4s, and (S)-4w exhibited highly potent CCR5 antagonistic activities (IC50=1.9, 1.7, 1.6 nM, respectively) and inhibitory effects (IC50=1.0, 2.8, 7.7 nM, respectively) in the HIV-1 envelope mediated membrane fusion assay, together with good pharmacokinetic properties in rats. In addition, we established the synthesis of (S)-4r and (S)-4w by asymmetric oxidation with titanium-(S)-(-)-1,1'-bi-2-naphthol complex. 相似文献
8.
Christopher G. Barber David C. Blakemore Jean-Yves Chiva Rachel L. Eastwood Donald S. Middleton Kerry A. Paradowski 《Bioorganic & medicinal chemistry letters》2009,19(4):1075-1079
The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity together with microsomal stability and only weak activity at the hERG ion channel. 相似文献
9.
Gardner DS Santella JB Tebben AJ Batt DG Ko SS Traeger SC Welch PK Wadman EA Davies P Carter PH Duncia JV 《Bioorganic & medicinal chemistry letters》2008,18(2):586-595
Conformational analysis of the 3-benzylpiperidine in CCR3 antagonist clinical candidate 1 (BMS-639623) predicts that the benzylpiperidine may be replaced by acyclic, conformationally stabilized, anti-1,2-disubstituted phenethyl- and phenpropylamines. Ab initio calculations, enantioselective syntheses, and evaluation in CCR3 binding and chemotaxis assays of anti-1-methyl-2-hydroxyphenethyl- and phenpropylamine-containing CCR3 antagonists support this conformational correlation. 相似文献
10.
Christopher G. Barber David C. Blakemore Jean-Yves Chiva Rachel L. Eastwood Donald S. Middleton Kerry A. Paradowski 《Bioorganic & medicinal chemistry letters》2009,19(5):1499-1503
Optimisation of a series of 4-piperidinyltriazoles led to the identification of compound 28a which showed good whole cell antiviral activity, excellent selectivity over the hERG ion channel and complete oral absorption. 相似文献
11.
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
12.
McBriar MD Clader JW Chu I Del Vecchio RA Favreau L Greenlee WJ Hyde LA Nomeir AA Parker EM Pissarnitski DA Song L Zhang L Zhao Z 《Bioorganic & medicinal chemistry letters》2008,18(1):215-219
The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of gamma-secretase inhibitors. Selected compounds showed significant reduction of Abeta levels upon oral dosing in a transgenic murine model of Alzheimer's disease. 相似文献
13.
Ettorre A D'Andrea P Mauro S Porcelloni M Rossi C Altamura M Catalioto RM Giuliani S Maggi CA Fattori D 《Bioorganic & medicinal chemistry letters》2011,21(6):1807-1809
Starting from in-house capped tripeptide libraries, we have developed two series of compounds as potent antagonists of the hNK2 receptor with a reduced peptide character. These two series maintained a crucial amide bond, which could not be methylated or substituted with classical isostere without a dramatic loss in binding affinity, very likely due conformational changes.We report here the planning, synthesis and evaluation of molecules belonging to the selected chemical series, which contain a strategically placed hydrogen bond acceptor. The aim of the work was to improve membrane permeability via the formation of an intramolecular hydrogen bonding, and at the same time to maintain the structural characteristics geometry and polarity of the amide linkage so as to retain a relevant binding affinity for the biological target. 相似文献
14.
Rémy C. Lemoine Ann C. Petersen Lina Setti Andreas Jekle Gabrielle Heilek André deRosier Changhua Ji Pamela Berry David M. Rotstein 《Bioorganic & medicinal chemistry letters》2010,20(16):4753-4756
The introduction of N-substituted pyrazoles in a new series of CCR5 antagonists was shown to substantially increase antiviral activity. 相似文献
15.
Tagat JR McCombie SW Steensma RW Lin S Nazareno DV Baroudy B Vantuno N Xu S Liu J 《Bioorganic & medicinal chemistry letters》2001,11(16):2143-2146
Optimization of the piperidino-piperazines 1 and 2 provided early leads 3 and 4, which showed good activity in the CCR5-RANTES binding assay and in antiviral assays. A systematic study around these structures showed that the 2(S)-methyl piperazine is essential for CCR5 affinity, which is further enhanced by forming the 2,6-dimethyl benzamide of the piperidine. 相似文献
16.
Hale JJ Budhu RJ Mills SG MacCoss M Gould SL DeMartino JA Springer MS Siciliano SJ Malkowitz L Schleif WA Hazuda D Miller M Kessler J Danzeisen R Holmes K Lineberger J Carella A Carver G Emini EA 《Bioorganic & medicinal chemistry letters》2002,12(20):2997-3000
Incorporation of acidic functional groups into a lead CCR5 antagonist identified from a targeted combinatorial library resulted in compounds with enhanced anti-HIV-1 activity and attenuated L-type calcium channel affinity. 相似文献
17.
Thrombin receptor (PAR-1) antagonists. Solid-phase synthesis of indole-based peptide mimetics by anchoring to a secondary amide 总被引:1,自引:0,他引:1
Zhang HC McComsey DF White KB Addo MF Andrade-Gordon P Derian CK Oksenberg D Maryanoff BE 《Bioorganic & medicinal chemistry letters》2001,11(16):2105-2109
A novel, 10-step, solid-phase method, based on a secondary amide linker, was developed to construct a diverse library of indole-based SFLLR peptide mimetics as thrombin receptor (protease-activated receptor 1, PAR-1) antagonists. The key steps include stepwise reductive alkylation, urea formation, and Mannich reaction. Screening of the library led to a quick development of the SAR and the significant improvement of PAR-1 activity. 相似文献
18.
Hale JJ Budhu RJ Mills SG MacCoss M Malkowitz L Siciliano S Gould SL DeMartino JA Springer MS 《Bioorganic & medicinal chemistry letters》2001,11(11):1437-1440
A series of 1,3,4-trisubstituted pyrrolidines was discovered to have the ability to displace [(125)I]-MIP-1alpha from the CCR5 receptor expressed on Chinese hamster ovary (CHO) cell membranes. CCR5 activity was found to be dependent on the regiochemistry and the absolute stereochemistry of the pyrrolidine. 相似文献
19.
Palani A Shapiro S Clader JW Greenlee WJ Vice S McCombie S Cox K Strizki J Baroudy BM 《Bioorganic & medicinal chemistry letters》2003,13(4):709-712
The synthesis, SAR and biological evaluation of symmetrical amide analogues of our clinical candidate SCH 351125 are described. A series of potent and orally bioavailable CCR5 antagonists containing symmetrical 2,6-dimethyl isonicotinamides and 2, 6-dimethyl pyrimidines amides were generated with enhanced affinity for the CCR5 receptor. 相似文献
20.
Wang GZ Haile PA Daniel T Belot B Viet AQ Goodman KB Sha D Dowdell SE Varga N Hong X Chakravorty S Webb C Cornejo C Olzinski A Bernard R Evans C Emmons A Briand J Chung CW Quek R Lee D Gough PJ Sehon CA 《Bioorganic & medicinal chemistry letters》2011,21(24):7291-7294
A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood. 相似文献