共查询到20条相似文献,搜索用时 0 毫秒
1.
Ariamala Gopalsamy Greg Ciszewski Mengxiao Shi Dan Berger Yongbo Hu Frederick Lee Larry Feldberg Eileen Frommer Steven Kim Karen Collins Donald Wojciechowicz Robert Mallon 《Bioorganic & medicinal chemistry letters》2009,19(24):6890-6892
Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases. 相似文献
2.
Ariamala Gopalsamy Greg Ciszewski Yongbo Hu Frederick Lee Larry Feldberg Eileen Frommer Steven Kim Karen Collins Donald Wojciechowicz Robert Mallon 《Bioorganic & medicinal chemistry letters》2009,19(10):2735-2738
B-Raf kinase plays a critical role in the Raf-MEK-ERK signaling pathway and inhibitors of B-Raf could be used in the treatment of melanomas, colorectal cancer, and other Ras related human cancers. We have identified novel small molecule pyrazolo[1,5-a]pyrimidine derivatives as B-Raf kinase inhibitors. Structure–activity relationship was generated for various regions of the scaffold to improve the biochemical profile. 相似文献
3.
Williamson DS Parratt MJ Bower JF Moore JD Richardson CM Dokurno P Cansfield AD Francis GL Hebdon RJ Howes R Jackson PS Lockie AM Murray JB Nunns CL Powles J Robertson A Surgenor AE Torrance CJ 《Bioorganic & medicinal chemistry letters》2005,15(4):863-867
The protein structure guided design of a series of pyrazolo[1,5-a]pyrimidines with high potency for human cyclin-dependent kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK-3beta and other kinases. 相似文献
4.
Cheung M Harris PA Badiang JG Peckham GE Chamberlain SD Alberti MJ Jung DK Harris SS Bramson NH Epperly AH Stimpson SA Peel MR 《Bioorganic & medicinal chemistry letters》2008,18(20):5428-5430
A series of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized as novel potent p38 kinase inhibitors. Our approaches towards improving in vitro metabolism and in vivo pharmacokinetic properties of the series are described. 相似文献
5.
Mukaiyama H Nishimura T Kobayashi S Komatsu Y Kikuchi S Ozawa T Kamada N Ohnota H 《Bioorganic & medicinal chemistry》2008,16(2):909-921
To improve the in vitro potency of the c-Src inhibitor 1a and to address its hERG liability, a structure-activity study was carried out, focusing on two regions of the lead compound. The blockade of the delayed cardiac current rectifier K(+) (I(Kr)) channel was overcome by replacing the ethylenediamino group with an amino alcohol group at the 7-position. In addition, modifying the substituents at the 5-position and the side chain groups on the amino alcohols at the 7-position enhanced the intracellular c-Src inhibitory activity and increased central nervous system (CNS) penetration. In the present study, 6l exhibited significant in vivo efficacy in a middle cerebral artery (MCA) occlusion model in rats. 相似文献
6.
Xiaojing Wang Steven Magnuson Rich Pastor Eric Fan Huiyong Hu Vickie Tsui Wei Deng Jeremy Murray Micah Steffek Heidi Wallweber John Moffat Jason Drummond Grace Chan Eric Harstad Allen J. Ebens 《Bioorganic & medicinal chemistry letters》2013,23(11):3149-3153
Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms. 相似文献
7.
Paruch K Dwyer MP Alvarez C Brown C Chan TY Doll RJ Keertikar K Knutson C McKittrick B Rivera J Rossman R Tucker G Fischmann TO Hruza A Madison V Nomeir AA Wang Y Lees E Parry D Sgambellone N Seghezzi W Schultz L Shanahan F Wiswell D Xu X Zhou Q James RA Paradkar VM Park H Rokosz LR Stauffer TM Guzi TJ 《Bioorganic & medicinal chemistry letters》2007,17(22):6220-6223
Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model. 相似文献
8.
Mark W. Ledeboer Albert C. Pierce John P. Duffy Huai Gao David Messersmith Francesco G. Salituro Suganthini Nanthakumar Jon Come Harmon J. Zuccola Lora Swenson Dina Shlyakter Sudipta Mahajan Thomas Hoock Bin Fan Wan-Jung Tsai Elaine Kolaczkowski Scott Carrier James K. Hogan Richard Zessis S. Pazhanisamy Youssef L. Bennani 《Bioorganic & medicinal chemistry letters》2009,19(23):6529-6533
Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2. 相似文献
9.
Nina Gommermann Peter Buehlmayer Anette von Matt Werner Breitenstein Keiichi Masuya Bernard Pirard Pascal Furet Sandra W. Cowan-Jacob Gisbert Weckbecker 《Bioorganic & medicinal chemistry letters》2010,20(12):3628-3631
A novel series of pyrazolo[1,5a]pyrimidines was optimized to target lymphocyte-specific kinase (Lck). An efficient synthetic route was developed and SAR studies toward activity and selectivity are described, leading to Lck inhibitors with enzymatic, cellular and in vivo potency. 相似文献
10.
Griffith DA Hargrove DM Maurer TS Blum CA De Lombaert S Inthavongsay JK Klade LE Mack CM Rose CR Sanders MJ Carpino PA 《Bioorganic & medicinal chemistry letters》2011,21(9):2641-2645
A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H-pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents. 相似文献
11.
Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors 总被引:3,自引:0,他引:3
Fraley ME Hoffman WF Rubino RS Hungate RW Tebben AJ Rutledge RZ McFall RC Huckle WR Kendall RL Coll KE Thomas KA 《Bioorganic & medicinal chemistry letters》2002,12(19):2767-2770
We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC(50)=19 nM), respectively. The synthesis and SAR of these compounds are described. 相似文献
12.
Huang CQ Wilcoxen KM Grigoriadis DE McCarthy JR Chen C 《Bioorganic & medicinal chemistry letters》2004,14(15):3943-3947
A series of 3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines was designed and synthesized as antagonists for the corticotrophin-releasing factor-1 (CRF(1)) receptor. Several compounds such as 20c (K(i)=10 nM) exhibited good binding affinities at the CRF(1) receptor. In addition, 20c had adequate solubility in water. 相似文献
13.
Alberti MJ Auten EP Lackey KE McDonald OB Wood ER Preugschat F Cutler GJ Kane-Carson L Liu W Jung DK 《Bioorganic & medicinal chemistry letters》2005,15(16):3778-3781
The discovery, synthesis, potential binding mode, and in vitro kinase profile of several pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines as potent kinase inhibitors are discussed. 相似文献
14.
Ren L Laird ER Buckmelter AJ Dinkel V Gloor SL Grina J Newhouse B Rasor K Hastings G Gradl SN Rudolph J 《Bioorganic & medicinal chemistry letters》2012,22(2):1165-1168
Herein we describe a novel series of ATP competitive B-Raf inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with improved physicochemical and pharmacokinetic properties. 相似文献
15.
Nie Z Perretta C Erickson P Margosiak S Almassy R Lu J Averill A Yager KM Chu S 《Bioorganic & medicinal chemistry letters》2007,17(15):4191-4195
The structure-based design, synthesis, and anticancer activity of novel inhibitors of protein kinase CK2 are described. Using pyrazolo[1,5-a][1,3,5]triazine as the core scaffold, a structure-guided series of modifications provided pM inhibitors with microM-level cytotoxic activity in cell-based assays with prostate and colon cancer cell lines. 相似文献
16.
Nie Z Perretta C Erickson P Margosiak S Lu J Averill A Almassy R Chu S 《Bioorganic & medicinal chemistry letters》2008,18(2):619-623
A series of macrocyclic derivatives has been designed and synthesized based on the X-ray co-crystal structures of pyrazolo[1,5-a] [1,3,5]triazines with corn CK2 (cCK2) protein. Bioassays demonstrated that these macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds are potent CK2 inhibitors with K(i) around 1.0 nM and strongly inhibit cancer cell growth with IC(50) as low as approximately 100 nM. 相似文献
17.
Saito T Obitsu T Kondo T Matsui T Nagao Y Kusumi K Matsumura N Ueno S Kishi A Katsumata S Kagamiishi Y Nakai H Toda M 《Bioorganic & medicinal chemistry》2011,19(18):5432-5445
To identify an orally active corticotropin-releasing factor 1 receptor antagonist, a series of 6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives were designed, synthesized and evaluated. An in vitro study followed by in vivo and pharmacokinetic studies of these heterotricyclic compounds led us to the discovery of an orally active CRF1 receptor antagonist. The results of a structure-activity relationship study are presented. 相似文献
18.
Jian-kang Jiang Xiuli Huang Khalida Shamim Paresma R. Patel Arthur Lee Amy Q. Wang Kimloan Nguyen Gregory Tawa Gregory D. Cuny Paul B. Yu Wei Zheng Xin Xu Philip Sanderson Wenwei Huang 《Bioorganic & medicinal chemistry letters》2018,28(20):3356-3362
The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties. 相似文献
19.
Michael P. Dwyer Kartik Keertikar Kamil Paruch Carmen Alvarez Marc Labroli Cory Poker Thierry O. Fischmann Rosemary Mayer-Ezell Richard Bond Yan Wang Rita Azevedo Timothy J. Guzi 《Bioorganic & medicinal chemistry letters》2013,23(22):6178-6182
The synthesis and hit-to-lead SAR development from a pyrazolo[1,5-a]pyrimidine-derived hit 5 to the identification of a series of potent, pan–Pim inhibitors such as 11j are described. 相似文献
20.
Packard GK Papa P Riggs JR Erdman P Tehrani L Robinson D Harris R Shevlin G Perrin-Ninkovic S Hilgraf R McCarrick MA Tran T Fleming Y Bai A Richardson S Katz J Tang Y Leisten J Moghaddam M Cathers B Zhu D Sakata S 《Bioorganic & medicinal chemistry letters》2012,22(1):747-752
The serine/threonine specific protein kinase B-Raf is part of the MAPK pathway and is an interesting oncology target. We have identified thieno[2,3-d]pyrimidines as a core scaffold of small molecule B-Raf inhibitors. The SAR of analogs in this series will be described. 相似文献