共查询到20条相似文献,搜索用时 0 毫秒
1.
Ogino Y Ohtake N Kobayashi K Kimura T Fujikawa T Hasegawa T Noguchi K Mase T 《Bioorganic & medicinal chemistry letters》2003,13(13):2167-2172
Optimization of the amine part of our original muscarinic M(3) receptor antagonist 1 was performed to identify M(3) receptor antagonists that are superior to 1. Compounds carrying a variety of diamine moieties without hydrophobic substituent on the nitrogen atom were screened against the binding affinity for the M(3) receptor and the selectivity for M(3) over the M(1) and M(2) receptors. This process led to a 4-aminopiperidinamide (2l) with a K(i) value of 5.1 nM and with a selectivity of the M(3) receptor that was 46-fold greater than that of the M(2) receptor. Further derivatization of 2l by inserting a spacer group or by incorporating alkyl group(s) into the amine part resulted in the identification of an 4-(aminoethyl)piperidinamide 2l-b with a K(i) value of 3.7 nM for the M(3) receptor and a selectivity for the M(3) receptor that was 170-fold greater than that of the M(2) receptor. 相似文献
2.
Nalin L. Subasinghe James Lanter Thomas Markotan Evan Opas Sandra McKenney Carl Crysler Cuifen Hou John O’Neill Dana Johnson Zhihua Sui 《Bioorganic & medicinal chemistry letters》2013,23(4):1063-1069
The inflammatory response associated with the activation of C–C chemokine receptor CCR2 via it’s interaction with the monocyte chemoattractant protein-1 (MCP-1, CCL2) has been implicated in many disease states, including rheumatoid arthritis, multiple sclerosis, atherosclerosis, asthma and neuropathic pain. Small molecule antagonists of CCR2 have been efficacious in animal models of inflammatory disease, and have been advanced into clinical development. The necessity to attenuate hERG binding appears to be a common theme for many of the CCR2 antagonist scaffolds appearing in the literature, presumably due the basic hydrophobic motif present in all of these molecules. Following the discovery of a novel cyclohexyl azetidinylamide CCR2 antagonist scaffold, replacement of the amide bond with heterocyclic rings was explored as a strategy for reducing hERG binding and improving pharmacokinetic properties. 相似文献
3.
Cumming JG Cooper AE Grime K Logan CJ McLaughlin S Oldfield J Shaw JS Tucker H Winter J Whittaker D 《Bioorganic & medicinal chemistry letters》2005,15(22):5012-5015
SAR and DMPK studies led to the identification of substituted N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides as potent and orally bioavailable ligands for the human CCR5 chemokine receptor. 相似文献
4.
Cumming JG Brown SJ Cooper AE Faull AW Flynn AP Grime K Oldfield J Shaw JS Shepherd E Tucker H Whittaker D 《Bioorganic & medicinal chemistry letters》2006,16(13):3533-3536
SAR and PK studies led to the identification of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl] propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide as a highly potent and selective ligand for the human CCR5 chemokine receptor with good oral pharmacokinetic properties. 相似文献
5.
Dhanak D Christmann LT Darcy MG Keenan RM Knight SD Lee J Ridgers LH Sarau HM Shah DH White JR Zhang L 《Bioorganic & medicinal chemistry letters》2001,11(11):1445-1450
Highly potent CCR3 antagonists have been developed from a previously reported series of phenylalanine ester-based leads. Solution-phase, parallel synthesis optimization was utilized to identify highly potent, functional CCR3 antagonists. 相似文献
6.
Moree WJ Kataoka K Ramirez-Weinhouse MM Shiota T Imai M Sudo M Tsutsumi T Endo N Muroga Y Hada T Tanaka H Morita T Greene J Barnum D Saunders J Kato Y Myers PL Tarby CM 《Bioorganic & medicinal chemistry letters》2004,14(21):5413-5416
Structure-activity relationships (SAR) of a weakly active class of CCR2b inhibitors were utilized to initiate a lead evolution program employing the Drug Discovery Engine. Several alternative structural series have been discovered that display nanomolar activity in the CCR2b binding and CCR2b-mediated chemotaxis assays. 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.
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
9.
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
10.
Napier SE Letourneau JJ Ansari N Auld DS Baker J Best S Campbell-Wan L Chan JH Craighead M Desai H Goan KA Ho KK Hulskotte EG MacSweeney CP Milne R Morphy JR Neagu I Ohlmeyer MH Peeters AW Presland J Riviello C Ruigt GS Thomson FJ Zanetakos HA Zhao J Webb ML 《Bioorganic & medicinal chemistry letters》2011,21(6):1871-1875
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b (V3) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction. 相似文献
11.
Todd A. Brugel Reed W. Smith Michael Balestra Christopher Becker Thalia Daniels Gerard M. Koether Scott R. Throner Laura M. Panko Dean G. Brown Ruifeng Liu John Gordon Matthew F. Peters 《Bioorganic & medicinal chemistry letters》2010,20(18):5405-5410
Further structure activity relationship studies on a previously reported 8-azabicyclo[3.2.1]octan-3-yloxy-benzamide series of potent and selective kappa opioid receptor antagonists is discussed. Modification of the pendant N-substitution to include a cyclohexylurea moiety produced analogs with greater in vitro opioid and hERG selectivity such as 12 (κ IC50 = 172 nM, μ:κ ratio = 93, δ:κ ratio = >174, hERG IC50 = >33 μM). Changes to the linker conformation and identity as well as to the benzamide ring moiety were also investigated. 相似文献
12.
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
13.
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
14.
Wei RG Arnaiz DO Chou YL Davey D Dunning L Lee W Lu SF Onuffer J Ye B Phillips G 《Bioorganic & medicinal chemistry letters》2007,17(1):231-234
High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists. 相似文献
15.
Spyvee MR Zhang H Hawkins LD Chow JC 《Bioorganic & medicinal chemistry letters》2005,15(24):5494-5498
Novel synthetic phospholipid compound 1 was discovered to be an antagonist of human toll-like receptor 2 (TLR2) signaling. In a preliminary SAR campaign we synthesized several analogues of 1 and found that considerable structural changes could be made without loss of TLR2 antagonistic activity. 相似文献
16.
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
17.
Napier SE Letourneau JJ Ansari N Auld DS Baker J Best S Campbell-Wan L Chan R Craighead M Desai H Ho KK MacSweeney C Milne R Richard Morphy J Neagu I Ohlmeyer MH Pick J Presland J Riviello C Zanetakos HA Zhao J Webb ML 《Bioorganic & medicinal chemistry letters》2011,21(12):3813-3817
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction. 相似文献
18.
Lagu B Gerchak C Pan M Hou C Singer M Malaviya R Matheis M Olini G Cavender D Wachter M 《Bioorganic & medicinal chemistry letters》2007,17(15):4382-4386
A number of compounds bearing a quaternary ammonium moiety were found to be antagonists with nanomolar binding affinity for the chemokine receptor-2. The structure-activity relationships in the series are described herein along with some detailed characterization of the interesting compounds. 相似文献
19.
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
20.
Sehon C McClure K Hack M Morton M Gomez L Li L Barrett TD Shankley N Breitenbucher JG 《Bioorganic & medicinal chemistry letters》2006,16(1):77-80
High-throughput screening revealed compound 1 as a potent antagonist of the CCK(1) receptor. Here, we disclose the synthesis of combinatorial libraries by solid-phase synthesis on Kenner 'safety catch' resin. Additive QSAR models were used to determine a lack of consistent additive SAR within the matrix. 相似文献