共查询到20条相似文献,搜索用时 15 毫秒
1.
Liang GB Qian X Biftu T Feng D Fisher M Crumley T Darkin-Rattray SJ Dulski PM Gurnett A Leavitt PS Liberator PA Misura AS Samaras S Tamas T Schmatz DM Wyvratt M 《Bioorganic & medicinal chemistry letters》2005,15(20):4570-4573
Diaryl-(4-piperidinyl)-pyrrole derivatives bearing hydroxylated N-alkyl substituents have been synthesized and evaluated as anticoccidial agents. High potency in Et-PKG inhibition and broad-spectrum anticoccidial activities have been observed on compounds, such as 4b and 5h, which are fully efficacious in vivo at 50 ppm in feed. 相似文献
2.
Liang GB Qian X Feng D Fisher M Crumley T Darkin-Rattray SJ Dulski PM Gurnett A Leavitt PS Liberator PA Misura AS Samaras S Tamas T Schmatz DM Wyvratt M Biftu T 《Bioorganic & medicinal chemistry letters》2008,18(6):2019-2022
Diaryl-(4-piperidinyl)-pyrrole derivatives bearing cyclic amine substituents have been synthesized and evaluated as anticoccidial agents. Improvements in potency of Et-PKG inhibition, such as azetidine derivative 3a, and broad spectrum anticoccidial activities in feed, such as morpholine derivative 8c, have been achieved. 相似文献
3.
Qian X Liang GB Feng D Fisher M Crumley T Rattray S Dulski PM Gurnett A Leavitt PS Liberator PA Misura AS Samaras S Tamas T Schmatz DM Wyvratt M Biftu T 《Bioorganic & medicinal chemistry letters》2006,16(10):2817-2821
2-(4-Fluorophenyl)-3-(4-pyridinyl)-5-substituted pyrroles were prepared and evaluated as anticoccidial agents in both in vitro and in vivo assays. Among the compounds evaluated, the dimethylamine-substituted pyrrole 19a is the most potent inhibitor of Eimeria tenella PKG (cGMP-dependent protein kinase). Further SAR studies on the side chain of the 2-pyrrolidine nitrogen did not enhance in vivo anticoccidial activity. 相似文献
4.
Liang GB Qian X Feng D Fisher M Brown CM Gurnett A Leavitt PS Liberator PA Misura AS Tamas T Schmatz DM Wyvratt M Biftu T 《Bioorganic & medicinal chemistry letters》2007,17(13):3558-3561
Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed. 相似文献
5.
Song X Chen W Lin L Ruiz CH Cameron MD Duckett DR Kamenecka TM 《Bioorganic & medicinal chemistry letters》2011,21(23):7072-7075
The design and synthesis of a novel series of c-jun N-terminal kinase (JNK3) inhibitors is described. The development and optimization of the 2-phenoxypyridine series was carried out from an earlier pyrimidine series of JNK1 inhibitors. Through the optimization of the scaffold 2, several potent compounds with good in vivo profiles were discovered. 相似文献
6.
Qing Ye Ji Cao Xinglu Zhou Dan Lv Qiaojun He Bo Yang Yongzhou Hu 《Bioorganic & medicinal chemistry》2009,17(13):4763-4772
A series of novel 7-azaindazolyl-indolyl-maleimides were synthesized and evaluated for their antiproliferative activity in vitro against various human cancer cell lines and protein kinase C inhibitory activity. Compounds 8a–c, 8e and 14a were the most promising compounds against K562, A549, ECA-109, KB and SMMC-7721 cell lines in vitro. Compounds 9a–j showed moderate PKC inhibition. Further mechanism of action studies revealed that the antiproliferative activity of compound 8b in KB cells might involve the mitochondria-mediated apoptosis pathway. 相似文献
7.
Andrew Scribner Joseph A. Moore Gilles Ouvry Michael Fisher Matthew Wyvratt Penny Leavitt Paul Liberator Anne Gurnett Chris Brown John Mathew Donald Thompson Dennis Schmatz Tesfaye Biftu 《Bioorganic & medicinal chemistry letters》2009,19(5):1517-1521
Novel 2,3-diarylindoles bearing an amine substituent at the indole 5- and 6-positions have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 27. 相似文献
8.
Alam M Beevers RE Ceska T Davenport RJ Dickson KM Fortunato M Gowers L Haughan AF James LA Jones MW Kinsella N Lowe C Meissner JW Nicolas AL Perry BG Phillips DJ Pitt WR Platt A Ratcliffe AJ Sharpe A Tait LJ 《Bioorganic & medicinal chemistry letters》2007,17(12):3463-3467
The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. 相似文献
9.
Haddach M Pierre F Regan CF Borsan C Michaux J Stefan E Kerdoncuff P Schwaebe MK Chua PC Siddiqui-Jain A Macalino D Drygin D O'Brien SE Rice WG Ryckman DM 《Bioorganic & medicinal chemistry letters》2012,22(1):45-48
Protein kinase CK2 is a potential drug target for many diseases including cancer and inflammation disorders. The crystal structure of clinical candidate CX-4945 1 with CK2 revealed an indirect interaction with the protein through hydrogen bonding between the NH of the 3-chlorophenyl amine and a water molecule. Herein, we investigate the relevance of this hydrogen bond by preparing several novel tricyclic derivatives lacking a NH moiety at the same position. This SAR study allowed the discovery of highly potent CK2 inhibitors. 相似文献
10.
《Bioorganic & medicinal chemistry letters》2014,24(1):161-164
The design and synthesis of isoxazole 3 is described, a potent JNK inhibitor with two fold selectivity over p38. Optimization of this scaffold led to compounds 27 and 28 which showed greatly improved selectivity over p38 by maintaining the JNK3 potency of compound 3. Extensive SAR studies will be described as well as preliminary in vivo data of the two lead compounds. 相似文献
11.
Youseung Shin Weiming Chen Jeff Habel Derek Duckett Yuan Yuan Ling Marcel Koenig Yuanjun He Tomas Vojkovsky Philip LoGrasso Theodore M. Kamenecka 《Bioorganic & medicinal chemistry letters》2009,19(12):3344-3347
A novel series of c-jun N-terminal kinase (JNK) inhibitors were designed and developed from a high-throughput-screening hit. Through the optimization of the piperazine amide 1, several potent compounds were discovered. The X-ray crystal structure of 4g showed a unique binding mode different from other well known JNK3 inhibitors. 相似文献
12.
An unusual monomeric cGMP-dependent protein kinase, enriched in cilia, was isolated from Paramecium cilia and whole cells. Cilia and whole cell extracts had relatively high ratios of cGMP-dependent to cAMP-dependent protein kinase activity (1:2). The calculated molecular weight of the native enzyme was 88,000. The enzyme was identified on sodium dodecyl sulfate-polyacrylamide gels as a 77,000 molecular weight band based on copurification of this protein with enzyme activity, 8-N3-[32P]cAMP labeling, and autophosphorylation. Based on the size of the native enzyme, it was concluded that the kinase is a monomer with cGMP-binding and catalytic activities on the same polypeptide. Dimer-sized cGMP-dependent protein kinase, like that of the well characterized mammalian enzyme, was never seen, despite stringent efforts to control proteolysis. The structure of the Paramecium cGMP-dependent protein kinase supports a model in which the dimeric vertebrate form of the enzyme evolved from an early monomeric form. The catalytic properties of the Paramecium enzyme differed in several respects from those of the mammalian enzyme: it could use GTP or ATP as the phosphoryl donor, it did not phosphorylate Kemptide effectively, and it had poor histone kinase activity with high Mg2+ concentrations. Quercertin, 5'-guanylyl imidodiphosphate, indomethacin, and the isoquinolinesulfonamide drug H7 inhibited Paramecium cGMP-dependent protein kinase activity. The enzyme had fast and slow binding sites (with kd values of 5-10 x 10(-3)s-1 and 0.44 x 10(-3)s-1) and showed an order of preference for cyclic nucleotides and cyclic nucleotide analogs similar to that of the mammalian enzyme. 相似文献
13.
Hui Pan Pham Van Khang Dong Dong Rui Wang Lei Ma 《Bioorganic & medicinal chemistry letters》2017,27(3):662-665
Sarsasapogenin, isolated from rhizomes of Anemarrhena asphodeloides, was found to be able to enhance memory. On the basis of the structure of Sarsasapogenin, a series of derivatives were synthesized and evaluated for their neuroprotective activity in PC12 cells and NO production inhibitory activity in RAW264.7 cell lines. The preliminary structure-activity relationship of them indicated that introduction of carbamate groups at the 3-hydroxyl position of sarsasapogenin might improve neuroprotective activity. Some synthesized derivatives such as AA3, AA4, AA9 and AA13 exhibited both notably neuroprotective activity and NO production inhibitory activity. 相似文献
14.
Illig CR Chen J Wall MJ Wilson KJ Ballentine SK Rudolph MJ DesJarlais RL Chen Y Schubert C Petrounia I Crysler CS Molloy CJ Chaikin MA Manthey CL Player MR Tomczuk BE Meegalla SK 《Bioorganic & medicinal chemistry letters》2008,18(5):1642-1648
The optimization of the arylamide lead 2 resulted in identification of a highly potent series of 2,4-disubstituted arylamides. Compound 8 (FMS kinase IC(50)=0.0008 microM) served as a proof-of-concept candidate in a collagen-induced model of arthritis in mice. 相似文献
15.
Woods KW Fischer JP Claiborne A Li T Thomas SA Zhu GD Diebold RB Liu X Shi Y Klinghofer V Han EK Guan R Magnone SR Johnson EF Bouska JJ Olson AM de Jong R Oltersdorf T Luo Y Rosenberg SH Giranda VL Li Q 《Bioorganic & medicinal chemistry》2006,14(20):6832-6846
A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (K(i)=0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other kinases. It is least selective for other members of the AGC family of kinases but is nonetheless 40-fold selective for Akt over PKA. The compound shows cellular activity and significantly slows tumor growth in vivo. 相似文献
16.
He Y Kamenecka TM Shin Y Song X Jiang R Noel R Duckett D Chen W Ling YY Cameron MD Lin L Khan S Koenig M LoGrasso PV 《Bioorganic & medicinal chemistry letters》2011,21(6):1719-1723
Quinazoline 3 was discovered as a novel c-jun N-terminal kinase (JNK) inhibitor with good brain penetration and pharmacokinetic (PK) properties. A number of analogs which were potent both in the biochemical and cellular assays were discovered. Quinazoline 13a was found to be a potent JNK3 inhibitor (IC50 = 40 nM), with >500-fold selectivity over p38, and had good PK and brain penetration properties. With these properties, 13a is considered a potential candidate for in vivo evaluation. 相似文献
17.
cGMP-dependent protein kinase (cGK) is a major cellular receptor of cGMP and plays important roles in cGMP-dependent signal transduction pathways. To isolate the components of the cGMP/cGK signaling pathway such as substrates and regulatory proteins of cGK, we employed the yeast two-hybrid system using cGK-Ialpha as a bait and isolated a novel male germ cell-specific 42-kDa protein, GKAP42 (42-kDa cGMP-dependent protein kinase anchoring protein). Although the N-terminal region (amino acids 1-66) of cGK-Ialpha is sufficient for the association with GKAP42, GKAP42 could not interact with cGK-Ibeta, cGK-II, or cAMP-dependent protein kinase. GKAP42 mRNA is specifically expressed in testis, where it is restricted to the spermatocytes and early round spermatids. Endogenous cGK-I is co-immunoprecipitated with anti-GKAP42 antibody from mouse testis tissue, suggesting that cGK-I physiologically interacts with GKAP42. Immunocytochemical observations revealed that GKAP42 is localized to the Golgi complex and that cGK-Ialpha is co-localized to the Golgi complex when coexpressed with GKAP42. Although both cGK-Ialpha and -Ibeta, but not cAMP-dependent protein kinase, phosphorylated GKAP42 in vitro, GKAP42 was a good substrate only for cGK-Ialpha in intact cells, suggesting that the association with kinase protein is required for the phosphorylation in vivo. Finally, we demonstrated that the kinase-deficient mutant of cGK-Ialpha stably associates with GKAP42 and that binding of cGMP to cGK-Ialpha facilitates their release from GKAP42. These findings suggest that GKAP42 functions as an anchoring protein for cGK-Ialpha and that cGK-Ialpha may participate in germ cell development through phosphorylation of Golgi-associated proteins such as GKAP42. 相似文献
18.
Kui Wu Jing Ai Qiufeng Liu TianTian Chen Ailing Zhao Xia Peng Yuanxiang Wang Yinchun Ji Qizheng Yao Yechun Xu Meiyu Geng Ao Zhang 《Bioorganic & medicinal chemistry letters》2012,22(20):6368-6372
Two series of new analogues were designed by replacing the quinoline scaffold of our earlier lead 2 (zgwatinib) with quinoxaline and pyrido[2,3-d]pyrimidine frameworks. Moderate c-Met inhibitory activity was observed in the quinoxaline series. Among the pyrido[2,3-d]pyrimidine series, compounds 13a–c possessing an O-linkage were inactive, whilst the N-linked analogues 15a–c retained c-Met inhibitory potency. Highest activity was observed in the 3-nitrobenzyl analog 15b that showed an IC50 value of 6.5 nM. Further structural modifications based on this compound were undergoing. 相似文献
19.
Paul S. Humphries Jennifer A. Lafontaine Charles S. Agree David Alexander Ping Chen Quyen-Quyen T. Do Lilian Y. Li Elizabeth A. Lunney Ranjan J. Rajapakse Karen Siegel Sergei L. Timofeevski Tianlun Wang David M. Wilhite 《Bioorganic & medicinal chemistry letters》2009,19(8):2099-2102
The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported. 相似文献
20.
Alan J. Henderson Mark Hadden Cheng Guo Neema Douglas Helene Decornez Mark R. Hellberg Andrew Rusinko Marsha McLaughlin Naj Sharif Colene Drace Raj Patil 《Bioorganic & medicinal chemistry letters》2010,20(3):1137-1140
Inhibition of rho kinase (ROCK) has been recognized as an important target for a number of diseases, including glaucoma. Herein we report SAR development around two hits from a kinase library that led to the discovery of the ROCK inhibitor compound 38. In vitro and in vivo analysis of this compound, including its effects in a monkey model of glaucoma will be discussed. 相似文献