共查询到20条相似文献,搜索用时 0 毫秒
1.
Biju P Taveras A Yu Y Zheng J Chao J Rindgen D Jakway J Hipkin RW Fossetta J Fan X Fine J Qiu H Merritt JR Baldwin JJ 《Bioorganic & medicinal chemistry letters》2008,18(1):228-231
A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-alpha and IL-8 mediated in vitro hPMN MPO release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed SAR has been discussed in these two closely related structures. 相似文献
2.
Yonghui Wang Jakob Busch-Petersen Feng Wang Terence J. Kiesow Todd L. Graybill Jian Jin Zheng Yang James J. Foley Gerald E. Hunsberger Dulcie B. Schmidt Henry M. Sarau Elizabeth A. Capper-Spudich Zining Wu Laura S. Fisher Michael S. McQueney Ralph A. Rivero Katherine L. Widdowson 《Bioorganic & medicinal chemistry letters》2009,19(1):114-118
A series of N-arylpiperazine camphor sulfonamides was discovered as novel CXCR3 antagonists. The synthesis, structure–activity relationships, and optimization of the initial hit that resulted in the identification of potent and selective CXCR3 antagonists are described. 相似文献
3.
Xiaohui Du Darin J. Gustin Xiaoqi Chen Jason Duquette Lawrence R. McGee Zhulun Wang Karen Ebsworth Kirk Henne Bryan Lemon Ji Ma Shichang Miao Emmanuel Sabalan Timothy J. Sullivan George Tonn Tassie L. Collins Julio C. Medina 《Bioorganic & medicinal chemistry letters》2009,19(17):5200-5204
A general way of improving the potency of CXCR3 antagonists with fused hetero-bicyclic cores was identified. Optimization efforts led to the discovery of a series of imidazo-pyrazine derivatives with improved pharmacokinetic properties in addition to increased potency. The efficacy of the lead compound 21 is evaluated in a mouse lung inflammation model. 相似文献
4.
Gijsen HJ Berthelot D De Cleyn MA Geuens I Brône B Mercken M 《Bioorganic & medicinal chemistry letters》2012,22(2):797-800
The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers. 相似文献
5.
Du X Chen X Mihalic JT Deignan J Duquette J Li AR Lemon B Ma J Miao S Ebsworth K Sullivan TJ Tonn G Collins TL Medina JC 《Bioorganic & medicinal chemistry letters》2008,18(2):608-613
A series of imidazole derivatives have been designed and optimized for CXCR3 antagonism, pharmacokinetic properties, and reduced formation of glutathione conjugates. Our efforts led to the discovery of potent CXCR3 antagonists with good pharmacokinetic properties. These compounds are useful tools for in vivo studies of CXCR3 function. 相似文献
6.
Watson RJ Allen DR Birch HL Chapman GA Hannah DR Knight RL Meissner JW Owen DA Thomas EJ 《Bioorganic & medicinal chemistry letters》2007,17(24):6806-6810
Development of a lead series of piperidinylurea CXCR3 antagonists has led to the identification of molecules with alternative linkages which retain good potency. A novel 5-(piperidin-4-yl)amino-1,2,4-thiadiazole derivative was found to have satisfactory in vitro metabolic stability and to be orally bioavailable in mice, giving high plasma concentrations and a half life of 5.4 h. 相似文献
7.
Wrobleski ML Reichard GA Paliwal S Shah S Tsui HC Duffy RA Lachowicz JE Morgan CA Varty GB Shih NY 《Bioorganic & medicinal chemistry letters》2006,16(14):3859-3863
A series of novel cyclobutane derivatives as potent and selective NK1 receptor antagonists is described. Several compounds in this series exhibited high in vitro binding affinity (Ki 相似文献
8.
9.
Wang Y Chackalamannil S Hu Z McKittrick BA Greenlee W Ruperto V Duffy RA Lachowicz JE 《Bioorganic & medicinal chemistry letters》2002,12(7):1087-1091
We have discovered highly potent, selective sulfide M(2) receptor antagonists with low molecular weight and different structural features compared with our phase I clinical candidate Sch 211803. Analogue 30 showed superior M(2) receptor selectivity profile over Sch 211803. More importantly, this study provided new leads for the discovery of M(2) receptor antagonists as potential drug candidates. 相似文献
10.
Chen X Mihalic J Deignan J Gustin DJ Duquette J Du X Chan J Fu Z Johnson M Li AR Henne K Sullivan T Lemon B Ma J Miao S Tonn G Collins T Medina JC 《Bioorganic & medicinal chemistry letters》2012,22(1):357-362
The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay. Compound 25 was identified as having the optimal balance of CXCR3 activity and pharmacokinetic properties across multiple pre-clinical species, which are reported herein. 相似文献
11.
Chao J Taveras AG Chao J Aki C Dwyer M Yu Y Purakkattle B Rindgen D Jakway J Hipkin W Fosetta J Fan X Lundell D Fine J Minnicozzi M Phillips J Merritt JR 《Bioorganic & medicinal chemistry letters》2007,17(13):3778-3783
A novel series of cyclobutenedione centered C(4)-alkyl substituted furanyl analogs was developed as potent CXCR2 and CXCR1 antagonists. Compound 16 exhibits potent inhibitory activities against IL-8 binding to the receptors (CXCR2 Ki=1 nM, IC(50)=1.3 nM; CXCR1 Ki=3 nM, IC(50)=7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5 nM, CXCR1 IC(50)=37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog. 相似文献
12.
André Alker Alfred Binggeli Andreas D. Christ Luke Green Hans Peter Maerki Rainer E. Martin Peter Mohr 《Bioorganic & medicinal chemistry letters》2010,20(15):4521-4525
Nicotinamides of benzyl-substituted 4-aminopiperidines and their seven-membered analogs of generic structure 2 and 2′ have been discovered as potent and selective SST5 antagonists. The activity (Ki) ranges from 2.4 to 436 nM. Most compounds exhibit decent physicochemical properties and follow a clear SAR pattern. Interestingly enough, the receptor is strongly enantiodiscriminating and binds in the amino-azepane-series only the (R)-enantiomer. 相似文献
13.
Shue HJ Chen X Shih NY Blythin DJ Paliwal S Lin L Gu D Schwerdt JH Shah S Reichard GA Piwinski JJ Duffy RA Lachowicz JE Coffin VL Liu F Nomeir AA Morgan CA Varty GB 《Bioorganic & medicinal chemistry letters》2005,15(17):3896-3899
A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein. 相似文献
14.
15.
《Bioorganic & medicinal chemistry letters》2020,30(17):127391
Nonpeptide sst2 agonists can provide a new treatment option for patients with acromegaly, carcinoid tumors, and neuroendocrine tumors. Our medicinal chemistry efforts have led to the discovery of novel 3,4-dihydroquinazoline-4-carboxamides as sst2 agonists. This class of molecules exhibits excellent human sst2 potency and selectivity against sst1, sst3, sst4 and sst5 receptors. Leading compound 3-(3-chloro-5-methylphenyl)-6-(3-fluoro-2-hydroxyphenyl)-N,7-dimethyl-N-{[(2S)-pyrrolidin-2-yl]methyl}-3,4-dihydroquinazoline-4-carboxamide (28) showed no inhibition of major CYP450 enzymes (2C9, 2C19, 2D6 and 3A4) and weak inhibition of the hERG channel. 相似文献
16.
N S Cutshall R Ursino K A Kucera J Latham N C Ihle 《Bioorganic & medicinal chemistry letters》2001,11(14):1951-1954
A series of nicotinamide N-oxides was synthesized and shown to be novel, potent, and selective antagonists of the CXCR2 receptor. Furthermore, these compounds showed significant functional activity against GRO-alpha-driven human neutrophil chemotaxis. Compounds of this class may be useful for the treatment of inflammatory, auto-immune, and allergic disorders. 相似文献
17.
Wang Y Busch-Petersen J Wang F Ma L Fu W Kerns JK Jin J Palovich MR Shen JK Burman M Foley JJ Schmidt DB Hunsberger GE Sarau HM Widdowson KL 《Bioorganic & medicinal chemistry letters》2007,17(14):3864-3867
A series of 3-arylamino-2H-1,2,4-benzothiadiazin-5-ol 1,1-dioxides were prepared and shown to be novel and selective antagonists of the CXCR2 receptor. Synthesis, structure and activity relationships, selectivity, and some developability properties are described. 相似文献
18.
Robarge MJ Bom DC Tumey LN Varga N Gleason E Silver D Song J Murphy SM Ekema G Doucette C Hanniford D Palmer M Pawlowski G Danzig J Loftus M Hunady K Sherf BA Mays RW Stricker-Krongrad A Brunden KR Harrington JJ Bennani YL 《Bioorganic & medicinal chemistry letters》2005,15(6):1749-1753
The chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH-2), also found on eosinophils and basophils, is a prostaglandin D2 receptor involved in the recruitment of these cell types during an inflammatory response. In this report, we describe the synthesis and optimization of a ramatroban isostere that is a selective and potent antagonist of CRTH-2 which may be useful in the treatment of certain diseases. 相似文献
19.
Fujimoto T Tomata Y Kunitomo J Hirozane M Marui S 《Bioorganic & medicinal chemistry letters》2011,21(21):6409-6413
To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity with an IC(50) value of 3nM with 450-fold selectivity against Orexin-1 Receptor (OX1R). 相似文献
20.
Wenying Chai Victoria D. Wong Diane Nepomuceno Pascal Bonaventure Timothy W. Lovenberg Nicholas I. Carruthers 《Bioorganic & medicinal chemistry letters》2013,23(14):4141-4144
A series of small molecules with a piperidinyl core were synthesized and tested for binding affinity (IC50) at human Neuropeptide Y Y2 receptor. Various amide related analogs (ureas, reversed amides, and sulfonamides) were evaluated. Several potent and selective NPY Y2 antagonists were identified. 相似文献