共查询到20条相似文献,搜索用时 0 毫秒
1.
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
2.
Robert J. Cherney Ruowei Mo Dayton T. Meyer Matthew E. Voss Yvonne C. Lo Gengjie Yang Persymphonie B. Miller Peggy A. Scherle Andrew J. Tebben Percy H. Carter Carl P. Decicco 《Bioorganic & medicinal chemistry letters》2009,19(13):3418-3422
Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative 54, which exhibited excellent binding (CCR2 IC50 = 1.3 nM) and functional antagonism (calcium flux IC50 = 0.5 nM and chemotaxis IC50 = 0.2 nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype. 相似文献
3.
Watson PS Jiang B Harrison K Asakawa N Welch PK Covington M Stowell NC Wadman EA Davies P Solomon KA Newton RC Trainor GL Friedman SM Decicco CP Ko SS 《Bioorganic & medicinal chemistry letters》2006,16(21):5695-5699
Linear unselective CCR3 antagonist leads with IC(50) values in the 200 nM range were converted into low nM binding compounds selective at CCR3 by moving the piperidine nitrogen substituent to the carbon at the 2-position of the ring. Substitution of the piperidine nitrogen with simple alkyl and acyl groups was found to improve the selectivity of this new compound class. In particular, N-{3-[(2S, 4R)-1-(propyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N'-(3-acetylphenyl)urea exhibited single digit nanomolar IC(50) values for CCR3 with >100-fold selectivity against an extensive counter screen panel. 相似文献
4.
Yang MG Xiao Z Shi Q Cherney RJ Tebben AJ De Lucca GV Santella JB Mo R Cvijic ME Zhao Q Barrish JC Carter PH 《Bioorganic & medicinal chemistry letters》2012,22(3):1384-1387
We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar binding affinity for CCR2. The in vitro structure-activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series. 相似文献
5.
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
6.
《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
7.
Jee Woong Lim Youna Oh Jong-Hoon Kim Min-Ho Oak Yongho Na Jung-Ok Lee Seung-Woo Lee Heeyeong Cho Woo-Kyu Park Gildon Choi Jongmin Kang 《Bioorganic & medicinal chemistry letters》2010,20(7):2099-2102
Novel 3-aminopyrrolidine derivatives were synthesized and evaluated for their antagonistic activity against human chemokine receptor 2. Structure–activity studies on 3-aminopyrrolidine incorporating heteroatomic carbocycle moieties led to piperidine compound 19, and piperazine compounds 42, 47 and 49 as highly potent hCCR2 antagonists. 相似文献
8.
Jiang R Song X Bali P Smith A Bayona CR Lin L Cameron MD McDonald PH Kenny PJ Kamenecka TM 《Bioorganic & medicinal chemistry letters》2012,22(12):3890-3894
A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure-activity relationships (SAR), installation of various groups at the 3-6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction. 相似文献
9.
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
10.
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
11.
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
12.
Carter PH Brown GD Friedrich SR Cherney RJ Tebben AJ Lo YC Yang G Jezak H Solomon KA Scherle PA Decicco CP 《Bioorganic & medicinal chemistry letters》2007,17(19):5455-5461
A new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure-activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three different substituents (benzylamine, carboxamide, and benzamide). Several of the acyclic compounds display 10-30 nM binding affinity for CCR2. Moreover, these antagonists are able to block both MCP-1-induced Ca(2+) flux and monocyte chemotaxis, and are selective for binding to CCR2 over CCR1 and CCR3. 相似文献
13.
Kettle JG Faull AW Barker AJ Davies DH Stone MA 《Bioorganic & medicinal chemistry letters》2004,14(2):405-408
Screening of the corporate database led to the discovery of a novel series of N-benzylindole-2-carboxylic acid CCR2b chemokine receptor antagonists. These compounds demonstrate high affinity and functional inhibition of the CCR2b receptor. A discussion of the structure-activity relationships is presented, together with evidence for a highly selective receptor binding profile. 相似文献
14.
Varnes JG Gardner DS Santella JB Duncia JV Estrella M Watson PS Clark CM Ko SS Welch P Covington M Stowell N Wadman E Davies P Solomon K Newton RC Trainor GL Decicco CP Wacker DA 《Bioorganic & medicinal chemistry letters》2004,14(7):1645-1649
The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s. 相似文献
15.
Xiang MA Chen RH Demarest KT Gunnet J Look R Hageman W Murray WV Combs DW Patel M 《Bioorganic & medicinal chemistry letters》2004,14(11):2987-2989
A novel series of spirobenzazepines was synthesized and evaluated for V1a and V2 receptor antagonist activity. Compounds 8b, 8i, and 8k have shown selective V1a receptor antagonist activity. Compounds 8p and 8q were shown to be dual V1a/V2 receptor antagonists. 相似文献
16.
Rainer E. Martin Peter Mohr Hans Peter Maerki Wolfgang Guba Christoph Kuratli Olivier Gavelle Alfred Binggeli Stefanie Bendels Rubén Alvarez-Sánchez André Alker Liudmila Polonchuk Andreas D. Christ 《Bioorganic & medicinal chemistry letters》2009,19(21):6106-6113
SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo. 相似文献
17.
Cole AG Stroke IL Qin LY Hussain Z Simhadri S Brescia MR Waksmunski FS Strohl B Tellew JE Williams JP Saunders J Appell KC Henderson I Webb ML 《Bioorganic & medicinal chemistry letters》2008,18(20):5420-5423
The discovery and synthesis of a series of (dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists from a small-molecule combinatorial library using a high-throughput calcium mobilization functional assay (HEK293-human OX2-R cell line) is described. Active compounds show a good correlation between high-throughput single concentration screening data and measured IC(50)s. Specific examples exhibit IC(50) values of approximately 20 nM using human orexin A as the peptide agonist for the orexin-2 receptor. 相似文献
18.
Witherington J Bordas V Cooper DG Forbes IT Gribble AD Ife RJ Berkhout T Gohil J Groot PH 《Bioorganic & medicinal chemistry letters》2001,11(16):2177-2180
The preparation and biological evaluation of a series of indolopiperidine CCR2B receptor antagonists possessing a conformationally restricted C-5 linker chain in combination with a restricted piperidine ring are described. Compared to the parent compound 1, analogue 8 shows a dramatic improvement in selectivity against a range of 5-HT and dopaminergic receptors. 相似文献
19.
Zhou C Guo L Parsons WH Mills SG MacCoss M Vicario PP Zweerink H Cascieri MA Springer MS Yang L 《Bioorganic & medicinal chemistry letters》2007,17(2):309-314
A series of racemic and homochiral alpha-aminothiazole-gamma-aminobutyroamides that display high affinities for human and murine CCR2 and functional antagonism by inhibition of monocyte recruitment are described. A representative example is (2S)-2-[2-(acetylamino)-1,3-thiazol-4-yl]-N-[3-methyl-5-(trifluoromethyl)benzyl]-4-(4-phenylpiperidin-1-yl)butanamide, which shows 5 nM affinity for human monocytes and CHO cells expressing the human CCR2b receptor. It also inhibited MCP-1 initiated chemotaxis of human monocytes with an IC50 of 0.69 nM. 相似文献
20.
Jin J Wang Y Wang F Shi D Erhard KF Wu Z Guida BF Lawrence SK Behm DJ Disa J Vaidya KS Evans C McMillan LJ Rivero RA Neeb MJ Douglas SA 《Bioorganic & medicinal chemistry letters》2008,18(9):2860-2864
A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described. 相似文献