共查询到20条相似文献,搜索用时 15 毫秒
1.
Duan M Peckham J Edelstein M Ferris R Kazmierski WM Spaltenstein A Wheelan P Xiong Z 《Bioorganic & medicinal chemistry letters》2010,20(24):7397-7400
Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series. 相似文献
2.
Maosheng Duan Christopher Aquino George F. Dorsey Robert Ferris Wieslaw M. Kazmierski 《Bioorganic & medicinal chemistry letters》2009,19(17):4988-4992
A series of 4,4-disubstituted cyclohexylamine based CCR5 antagonists has been designed and synthesized. Their antiviral structure–activity relationship has been extensively explored. 相似文献
3.
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
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.
Imamura S Kurasawa O Nara Y Ichikawa T Nishikawa Y Iida T Hashiguchi S Kanzaki N Iizawa Y Baba M Sugihara Y 《Bioorganic & medicinal chemistry》2004,12(9):2295-2306
We have previously reported the novel lead compound 1a as a CCR5 antagonist for treatment of HIV-1 infection. SAR studies on incorporating various acyl groups as a replacement for the 5-oxopyrrolidine-3-carbonyl group of the lead structure resulted in the discovery of N-[3-(4-benzylpiperidin-1-yl)propyl]-N,N'-diphenylurea (4a) with significantly improved CCR5 binding affinity. Substitutions (4-Cl, 4e,f; 4-Me, 4i) on the N'-phenyl ring further increased the binding affinity. Introduction of polar substituents on the phenyl ring of the 4-benzylpiperidine moiety enhanced the inhibitory activity of the HIV-1 envelope-mediated membrane fusion (4v,w), suggesting that polar substituents at this position can interfere effectively with HIV-1 cell entry. 相似文献
6.
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
7.
Allen S Newhouse B Anderson AS Fauber B Allen A Chantry D Eberhardt C Odingo J Burgess LE 《Bioorganic & medicinal chemistry letters》2004,14(7):1619-1624
Substituted thiazolidinones were identified as CCR4 antagonists from high throughput screening. Subsequent lead optimization efforts resulted in defined structure-activity relationships and the identification of potent antagonists (compounds 90 and 91) that inhibited the chemotaxis of Th2 T-cells in vitro. 相似文献
8.
M L Barreca A Chimirri L De Luca A M Monforte P Monforte A Rao M Zappalà J Balzarini E De Clercq C Pannecouque M Witvrouw 《Bioorganic & medicinal chemistry letters》2001,11(13):1793-1796
Design, synthesis and anti-HIV activity of a series of 2,3-diaryl-1,3-thiazolidin-4-ones are reported. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations thereby acting as non-nucleoside HIV-1 RT inhibitors (NNRTIs). SAR studies evidenced that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus largely influenced the in vitro anti-HIV activity of this new class of potent antiviral agents. 相似文献
9.
Nitta A Iura Y Tomioka H Sato I Morihira K Kubota H Morokata T Takeuchi M Ohta M Tsukamoto S Imaoka T Takahashi T 《Bioorganic & medicinal chemistry letters》2012,22(15):4951-4954
The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist. 相似文献
10.
Beck HP Kohn T Rubenstein S Hedberg C Schwandner R Hasslinger K Dai K Li C Liang L Wesche H Frank B An S Wickramasinghe D Jaen J Medina J Hungate R Shen W 《Bioorganic & medicinal chemistry letters》2008,18(3):1037-1041
The LPA(2) protein is overexpressed in many tumor cells. We report the optimization of a series of LPA(2) antagonists using calcium mobilization assay (aequorin assay) that led to the discovery of the first reported inhibitors selective for LPA(2). Key compounds were evaluated in vitro for inhibition of LPA(2) mediated Erk activation and proliferation of HCT-116 cells. These compounds could be used to evaluate the benefits of LPA(2) inhibition both in vitro and in vivo. 相似文献
11.
Rena Nishizawa Toshihiko Nishiyama Katsuya Hisaichi Keisuke Hirai Hiromu Habashita Yoshikazu Takaoka Hideaki Tada Kenji Sagawa Shiro Shibayama Kenji Maeda Hiroaki Mitsuya Hisao Nakai Daikichi Fukushima Masaaki Toda 《Bioorganic & medicinal chemistry》2010,18(14):5208-5223
Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure–activity relationship (SAR) study are presented. 相似文献
12.
Dorn CP Finke PE Oates B Budhu RJ Mills SG MacCoss M Malkowitz L Springer MS Daugherty BL Gould SL DeMartino JA Siciliano SJ 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(2):259-264
Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment. 相似文献
13.
Christian Harcken Christopher Sarko Can Mao John Lord Brian Raudenbush Hossein Razavi Pingrong Liu Alan Swinamer Darren Disalvo Thomas Lee Siqi Lin Alison Kukulka Heather Grbic Mita Patel Monica Patel Kim Fletcher David Joseph Della White David S. Thomson 《Bioorganic & medicinal chemistry letters》2019,29(3):435-440
A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties. 相似文献
14.
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
15.
Novikov MS Buckheit RW Temburnikar K Khandazhinskaya AL Ivanov AV Seley-Radtke KL 《Bioorganic & medicinal chemistry》2010,18(23):8310-8314
Pyrimidine analogs have long found use over a broad chemotherapeutic spectrum. In an effort to further explore the antiviral potential of several uracil derivatives previously synthesized in our laboratories, a series of benzylated pyrimidines were designed and synthesized. Introduction of the benzyl residue onto the 5-phenylaminouracil scaffold was carried out using 2,4-bis(trimethylsilyloxy)pyrimidine with the corresponding benzyl bromides. Similarly, 1-benzyl-5-(benzylamino)- and 1-benzyl-5-(phenethylamino)uracils were obtained via amination of 1-benzyl-5-bromouracils with benzylamine or phenylethylamine. The results of the broad screen antiviral studies revealed that compounds 5 and 11 exhibit promising inhibitory activity against HIV-1 in CEM-SS culture. A 50% protective effect was observed at concentrations of 11.9 and 9.5 μМ, respectively. Moreover, compounds 8 and 3 exhibited good inhibitory effects against EBV in АKАТА cell culture with EC50 values of 2.3 and 12 μM, respectively. The synthesis and biological studies are detailed herein. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2014,24(23):5493-5496
2-Aminopyrimidin-4(1H)-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1H)-ones led to the discovery of the novel and potent CXCR2 antagonist 3e. 2-Aminopyrimidin-4(1H)-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas. 相似文献
17.
《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
18.
Robert J. Cherney John B. Brogan Ruowei Mo Yvonne C. Lo Gengjie Yang Persymphonie B. Miller Peggy A. Scherle Bruce F. Molino Percy H. Carter Carl P. Decicco 《Bioorganic & medicinal chemistry letters》2009,19(3):597-601
A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC50 = 2.4 nM) and functional antagonism (calcium flux IC50 = 2.0 nM and chemotaxis IC50 = 5.1 nM). 相似文献
19.
Finke PE Meurer LC Oates B Mills SG MacCoss M Malkowitz L Springer MS Daugherty BL Gould SL DeMartino JA Siciliano SJ 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(2):265-270
(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X= H, 3-F, 3-Cl, 3-Me). 相似文献
20.
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