共查询到20条相似文献,搜索用时 15 毫秒
1.
Lynch CL Willoughby CA Hale JJ Holson EJ Budhu RJ Gentry AL Rosauer KG Caldwell CG Chen P Mills SG MacCoss M Berk S Chen L Chapman KT Malkowitz L Springer MS Gould SL DeMartino JA Siciliano SJ Cascieri MA Carella A Carver G Holmes K Schleif WA Danzeisen R Hazuda D Kessler J Lineberger J Miller M Emini EA 《Bioorganic & medicinal chemistry letters》2003,13(1):119-123
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics. 相似文献
2.
Shen DM Shu M Mills SG Chapman KT Malkowitz L Springer MS Gould SL DeMartino JA Siciliano SJ Kwei GY Carella A Carver G Holmes K Schleif WA Danzeisen R Hazuda D Kessler J Lineberger J Miller MD Emini EA 《Bioorganic & medicinal chemistry letters》2004,14(4):935-939
Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity. 相似文献
3.
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
4.
Kim D Wang L Hale JJ Lynch CL Budhu RJ Maccoss M Mills SG Malkowitz L Gould SL DeMartino JA Springer MS Hazuda D Miller M Kessler J Hrin RC Carver G Carella A Henry K Lineberger J Schleif WA Emini EA 《Bioorganic & medicinal chemistry letters》2005,15(8):2129-2134
A series of 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity. 相似文献
5.
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
6.
Lynch CL Hale JJ Budhu RJ Gentry AL Mills SG Chapman KT MacCoss M Malkowitz L Springer MS Gould SL DeMartino JA Siciliano SJ Cascieri MA Carella A Carver G Holmes K Schleif WA Danzeisen R Hazuda D Kessler J Lineberger J Miller M Emini EA 《Bioorganic & medicinal chemistry letters》2002,12(20):3001-3004
A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1. 相似文献
7.
Shu M Loebach JL Parker KA Mills SG Chapman KT Shen DM Malkowitz L Springer MS Gould SL DeMartino JA Siciliano SJ Salvo JD Lyons K Pivnichny JV Kwei GY Carella A Carver G Holmes K Schleif WA Danzeisen R Hazuda D Kessler J Lineberger J Miller MD Emini EA 《Bioorganic & medicinal chemistry letters》2004,14(4):947-952
Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity. 相似文献
8.
Hale JJ Budhu RJ Holson EB Finke PE Oates B Mills SG MacCoss M Gould SL DeMartino JA Springer MS Siciliano S Malkowitz L Schleif WA Hazuda D Miller M Kessler J Danzeisen R Holmes K Lineberger J Carella A Carver G Emini E 《Bioorganic & medicinal chemistry letters》2001,11(20):2741-2745
Investigations of the structure-activity relationships of 1,3,4-trisubstituted pyrrolidine human CCR5 receptor antagonists afforded orally bioavailable compounds with the ability to inhibit HIV replication in vitro. 相似文献
9.
Blizzard TA Dininno F Morgan JD Chen HY Wu JY Kim S Chan W Birzin ET Yang YT Pai LY Fitzgerald PM Sharma N Li Y Zhang Z Hayes EC Dasilva CA Tang W Rohrer SP Schaeffer JM Hammond ML 《Bioorganic & medicinal chemistry letters》2005,15(1):107-113
A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue. 相似文献
10.
Pinkerton AB Huang D Cube RV Hutchinson JH Struthers M Ayala JM Vicario PP Patel SR Wisniewski T DeMartino JA Vernier JM 《Bioorganic & medicinal chemistry letters》2007,17(3):807-813
We have identified and synthesized a series of diaryl substituted pyrazoles as potent antagonists of the chemokine receptor subtype 2. Structure-activity relationship studies directed toward improving the potency led to the discovery of 23 (IC50 = 6 nM). 相似文献
11.
Shen DM Shu M Willoughby CA Shah S Lynch CL Hale JJ Mills SG Chapman KT Malkowitz L Springer MS Gould SL DeMartino JA Siciliano SJ Lyons K Pivnichny JV Kwei GY Carella A Carver G Holmes K Schleif WA Danzeisen R Hazuda D Kessler J Lineberger J Miller MD Emini EA 《Bioorganic & medicinal chemistry letters》2004,14(4):941-945
Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered. 相似文献
12.
Pégurier C Collart P Danhaive P Defays S Gillard M Gilson F Kogej T Pasau P Van Houtvin N Van Thuyne M van Keulen B 《Bioorganic & medicinal chemistry letters》2007,17(15):4228-4231
The discovery and optimization of a novel class of potent CCR3 antagonists is described. Details of synthesis and SAR are given together with some ADME properties of selected compounds. An optimal balance between activities, physicochemical properties, and in vitro metabolic stability was reached by the proper choice of substituents. 相似文献
13.
Lu SF Chen B Davey D Dunning L Jaroch S May K Onuffer J Phillips G Subramanyam B Tseng JL Wei RG Wei M Ye B 《Bioorganic & medicinal chemistry letters》2007,17(7):1883-1887
The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, 1, with an IC(50) of 840 nM against the CCR5 receptor was identified using high-throughput screening. Optimization efforts led to the discovery of a novel piperidine series of CCR5 antagonists. In particular, the 4-hydroxypiperidine derivative, 6k, had improved potency against CCR5, and was a starting point for further optimization. SAR elaboration using parallel synthesis led to the identification of 10h, a potent CCR5 antagonist with an IC(50) of 11 nM. 相似文献
14.
Arslan S Loğoğlu E Oktemer A 《Journal of enzyme inhibition and medicinal chemistry》2006,21(2):211-214
The in vitro antibacterial and antifungal activities of the compounds synthesised from some 1,2,3,5-tetrahalogeno benzenes in presence of sodium piperidide and sodium pyrrolidide (2,6-dipiperidino-1,4-dihalogenobenzenes; 2,6-dipyrrolidino-1,4-dibromobenzene; 2,4,6-tripyrrolidino chlorobenzene; and 1,3-dipyrrolidino benzene) were investigated. The in vitro antimicrobial activities were screened against the standard strains: Staphylococcus aureus ATCC 25923 and Bacillus subtilis ATCC 6633 as Gram positive, Yersinia enterocolitica ATCC 1501, Escherichia coli ATCC 11230 and Klebsiella pneumoniae as Gram negative, and Candida albicans as yeast-like fungus. Compounds (3, 5, 6, 7) inhibited the growth of all the test strains at MIC values of 32-512 microg/ml. None of the four compounds (1, 2,4,8) studied showed antimicrobial activity against any of the test strains within the MIC range 0.25-512 micro/ml. 相似文献
15.
David M. Rotstein Stephen D. Gabriel Ferenc Makra Lubov Filonova Shelley Gleason Christine Brotherton-Pleiss Lina Q. Setti Alejandra Trejo-Martin Eun Kyung Lee Surya Sankuratri Changhua Ji Andre deRosier Marianna Dioszegi Gabrielle Heilek Andreas Jekle Pamela Berry Paul Weller Cheng-I. Mau 《Bioorganic & medicinal chemistry letters》2009,19(18):5401-5406
A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed. 相似文献
16.
17.
Purandare AV Wan H Somerville JE Burke C Vaccaro W Yang X McIntyre KW Poss MA 《Bioorganic & medicinal chemistry letters》2007,17(3):679-682
The design, synthesis, and SAR studies of 'core' variations led to identification of novel, selective, and potent small molecule antagonist (22) of the CC chemokine receptor-4 (CCR4) with improved in vitro activity and liability profile. Compound 22 was efficacious in a murine allergic inflammation model (ED50 approximately 10 mg/kg). 相似文献
18.
The CCR5 chemokine receptor has recently been found to play a crucial role in the viral entry stage of HIV infection and has therefore become an attractive potential target for anti-HIV therapeutics. On the other hand, the lack of CCR5 crystal structure data has impeded the development of structure-based CCR5 antagonist design. In this paper, we compare two three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) methods: Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) on a series of piperidine-based CCR5 antagonists as an alternative approach to investigate the interaction between CCR5 antagonists and their receptor. Superimposition of antagonist structures was performed using two alignment rules: atomic/centroid rms fit and rigid body field fit techniques. The 3D QSAR models were derived from a training set of 72 compounds, and were found to have predictive capability for a set of 19 holdout test compounds. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to biological activity in this series of compounds. Further analyses of these interaction-field contour maps also showed a high level of internal consistency. 相似文献
19.
Xia M Hou C Pollack S Brackley J DeMong D Pan M Singer M Matheis M Olini G Cavender D Wachter M 《Bioorganic & medicinal chemistry letters》2007,17(21):5964-5968
A series of phenyl piperidine derivatives possessing potent and selective CCR2 antagonist activity is reported. Structure-activity relationship (SAR) studies have established that incorporation of a second ring system adjacent to the aryl piperidine plays an important role in determining the CCR2 potency. Both a second piperidine ring and a 1,3-substituted cyclopentylamine have been probed as linkers. For the cyclopentylamine series, the 1S,3R-configuration exhibits much higher affinity for hCCR2 than the 1R,3S-configuration. Compound 3g shows good selectivity over CCR1, CCR3, 5-HT and has an excellent P450 profile. 相似文献
20.
Burdi DF Chi S Mattia K Harrington C Shi Z Chen S Jacutin-Porte S Bennett R Carson K Yin W Kansra V Gonzalo JA Coyle A Jaffee B Ocain T Hodge M LaRosa G Harriman G 《Bioorganic & medicinal chemistry letters》2007,17(11):3141-3145
The identification, optimization, and structure-activity relationship (SAR) of small-molecule CCR4 antagonists is described. An initial screening hit with micromolar potency was identified that was optimized to sub-micromolar binding potency by enantiomer resolution, halogenation of the naphthalene ring, and extension of the alkyl chain linker between the central piperidine ring and the terminal aryl group. An antagonist was identified that showed good cross-reactivity against the mouse receptor and inhibited CCR4-based cell recruitment in dose-dependent fashion. 相似文献