共查询到20条相似文献,搜索用时 15 毫秒
1.
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
2.
Hayes ME Breinlinger EC Wallace GA Grongsaard P Miao W McPherson MJ Stoffel RH Green DW Roth GP 《Bioorganic & medicinal chemistry letters》2008,18(7):2414-2419
Modification of a 2-iminobenzimidazole series derived from an HTS hit resulted in compounds with improved in-vitro species selectivity. Incorporation of an 8-quinoline amide and conformational rigidification of an aliphatic tether furnished potent compounds suitable for further lead optimization. 相似文献
3.
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
4.
Ho KK Auld DS Bohnstedt AC Conti P Dokter W Erickson S Feng D Inglese J Kingsbury C Kultgen SG Liu RQ Masterson CM Ohlmeyer M Rong Y Rooseboom M Roughton A Samama P Smit MJ Son E van der Louw J Vogel G Webb M Wijkmans J You M 《Bioorganic & medicinal chemistry letters》2006,16(10):2724-2728
An imidazolylpyrimidine was identified in a CXCR2 chemokine receptor antagonist screen and was optimized for potency, in vitro metabolic stability, and oral bioavailability. It was found that subtle structural modification within the series affected the oral bioavailability. Potent and orally available CXCR2 antagonists are herein reported. 相似文献
5.
Brian F. McGuinness Carolyn DiIanni Carroll Lisa Guise Zawacki Guizhen Dong Cangming Yang Doug W. Hobbs Biji Jacob-Samuel James W. Hall Chung-Her Jenh Joseph A. Kozlowski Gopinadhan N. Anilkumar Stuart B. Rosenblum 《Bioorganic & medicinal chemistry letters》2009,19(17):5205-5208
High-throughput screening of an encoded combinatorial aryl piperazine library led to the identification of a novel series of potent piperazinyl-piperidine based CXCR3 antagonists. Analogs of the initial hit were synthesized via solid and solution phase methods to probe the influence of structure on the CXCR3 binding of these molecules. Various functional groups were found to contribute to the overall potency and essential molecular features were identified. 相似文献
6.
Stefano Crosignani Marc Missotten Christophe Cleva Ruggero Dondi Yann Ratinaud Yves Humbert Ashis Baran Mandal Agnès Bombrun Christine Power André Chollet Amanda Proudfoot 《Bioorganic & medicinal chemistry letters》2010,20(12):3614-3617
The discovery of a novel series of CXCR3 antagonists is described. Starting from an HTS positive, iterative optimization gave potent compounds (IC50 15 nM in a chemotaxis assay). The strategy employed to improve the metabolic stability of these derivatives is described. 相似文献
7.
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
8.
Walters I Austin C Austin R Bonnert R Cage P Christie M Ebden M Gardiner S Grahames C Hill S Hunt F Jewell R Lewis S Martin I David Nicholls David Robinson 《Bioorganic & medicinal chemistry letters》2008,18(2):798-803
The CXCR2 SAR of a series of bicyclic antagonists such as the 2-aminothiazolo[4,5-d]pyrimidine 3b was investigated by systematic variation of the fused pyrimidine-based heterocyclic cores. Replacement of the aminothiazole ring with a 2-thiazolone alternative led to a series of thiazolo[4,5-d]pyrimidine-2(3H)-one antagonists with markedly improved biological and pharmacokinetic properties, which are suitable pharmacological tools to probe the in vivo effects of CXCR2 antagonism combined with the associated CCR2 activity. 相似文献
9.
Yu Y Dwyer MP Chao J Aki C Chao J Purakkattle B Rindgen D Bond R Mayer-Ezel R Jakway J Qiu H Hipkin RW Fossetta J Gonsiorek W Bian H Fan X Terminelli C Fine J Lundell D Merritt JR He Z Lai G Wu M Taveras A 《Bioorganic & medicinal chemistry letters》2008,18(4):1318-1322
Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives. 相似文献
10.
Jiwen Liu Zice Fu An-Rong Li Michael Johnson Liusheng Zhu Andrew Marcus Jay Danao Tim Sullivan George Tonn Tassie Collins Julio Medina 《Bioorganic & medicinal chemistry letters》2009,19(17):5114-5118
The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties. We will also discuss the efficacy of the lead compound 34 in a mouse model of cellular recruitment induced by bleomycin. 相似文献
11.
Merritt JR Rokosz LL Nelson KH Kaiser B Wang W Stauffer TM Ozgur LE Schilling A Li G Baldwin JJ Taveras AG Dwyer MP Chao J 《Bioorganic & medicinal chemistry letters》2006,16(15):4107-4110
A novel series of 3,4-diaminocyclobut-3-ene-1,2-diones was prepared and found to show potent inhibitory activity of CXCR2 binding and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Microsome stability and Caco2 studies were subsequently used to show that compounds of this chemotype are predicted to have good oral bioavailability and are thus suitable for pharmaceutical development. 相似文献
12.
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
13.
Nie H Widdowson KL Palovich MR Fu W Elliott JD Bryan DL Burman M Schmidt DB Foley JJ Sarau HM Busch-Petersen J 《Bioorganic & medicinal chemistry letters》2006,16(21):5513-5516
A series of N-(2-hydroxy-3-sulfonamidobenzene)-N'-arylcyanoguanidines was prepared. In general, these compounds proved to be potent antagonists of CXCR2 while the selectivity versus CXCR1 ranged from non-selective to >200-fold. 相似文献
14.
Li AR Johnson MG Liu J Chen X Du X Mihalic JT Deignan J Gustin DJ Duquette J Fu Z Zhu L Marcus AP Bergeron P McGee LR Danao J Lemon B Carabeo T Sullivan T Ma J Tang L Tonn G Collins TL Medina JC 《Bioorganic & medicinal chemistry letters》2008,18(2):688-693
A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo. 相似文献
15.
Because of its involvement in HIV entry, the chemokine receptor CXCR4 is an attractive target for antiretroviral drugs. Despite the large number of CXCR4 inhibitors studied, the 3D pharmacophore for binding to CXCR4 remains elusive, mainly as a result of conformational flexibility inherent in the identified ligands. In the present study, an exhaustive systematic exploration of the conformational space for a series of analogs of FC131, a cyclopentapeptide CXCR4 antagonist, has been performed. By comparing the resulting low-energy conformations using different sets of atoms, specific conformational features common only to the high/medium affinity compounds were identified. These features included the spatial arrangement of three pharmacophoric side chains as well as the orientation of a specific backbone amide bond. Together these features represent a minimalistic 3D pharmacophore model for binding of the cyclopentapeptide antagonists to CXCR4. The model enables rationalization of the experimental affinity data for this class of compounds as well as for the peptidomimetic KRH-1636. 相似文献
16.
Watson RJ Allen DR Birch HL Chapman GA Galvin FC Jopling LA Knight RL Meier D Oliver K Meissner JW Owen DA Thomas EJ Tremayne N Williams SC 《Bioorganic & medicinal chemistry letters》2008,18(1):147-151
The optimization of a series of 1-aryl-3-piperidinyl urea derivatives is described in which incorporation of tropenyl and homotropenyl moieties has led to significant improvements in activity and drug-like properties. Replacement of the central piperidine with an exo-tropanyl unit led to the identification of compound 15 which provides a combination of excellent potency against human and murine receptors, drug-like properties and pharmacokinetics, thus providing a valuable tool for the evaluation of CXCR3 antagonists in models of human disease. 相似文献
17.
Johnson M Li AR Liu J Fu Z Zhu L Miao S Wang X Xu Q Huang A Marcus A Xu F Ebsworth K Sablan E Danao J Kumer J Dairaghi D Lawrence C Sullivan T Tonn G Schall T Collins T Medina J 《Bioorganic & medicinal chemistry letters》2007,17(12):3339-3343
A series of quinazolinone-derived inhibitors of the CXCR3 receptor have been synthesized and their affinity for the receptor evaluated. Compounds were evaluated in a (125)I-IP10 displacement assay and in in vitro cell migration assays to IP10, ITAC, and MIG using human peripheral blood mononuclear cells. 相似文献
18.
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
19.
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
20.
Hayes ME Wallace GA Grongsaard P Bischoff A George DM Miao W McPherson MJ Stoffel RH Green DW Roth GP 《Bioorganic & medicinal chemistry letters》2008,18(5):1573-1576
High-throughput screening identified a low molecular weight antagonist of CXCR3 displaying micromolar activity in a membrane filtration-binding assay. Systematic modification of the benzimidazole core and tethered acetophenone moiety established tractable SAR of analogs with improved physicochemical properties and sub-micromolar activity across both human and murine receptors. 相似文献