共查询到20条相似文献,搜索用时 828 毫秒
1.
Saito T Obitsu T Minamoto C Sugiura T Matsumura N Ueno S Kishi A Katsumata S Nakai H Toda M 《Bioorganic & medicinal chemistry》2011,19(20):5955-5966
To identify structurally novel CRF1 receptor antagonists, a series of bicyclic core antagonists, pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines, imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines were designed, synthesized and evaluated as CRF1 receptor antagonists. Compounds 2-27 showed binding affinity (IC(50)=4.2-418 nM) and antagonist activity (EC(50)=4.0-889 nM). Compound 5 was found to show oral efficacy in an Elevated Plus Maze test in rats. Further chemical modification of them led us to discovery of the tricyclic core antagonists pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidines. The discovery process of these compounds is presented, as is the study of the structure-activity relationship. 相似文献
2.
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
3.
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
4.
Löber S Aboul-Fadl T Hübner H Gmeiner P 《Bioorganic & medicinal chemistry letters》2002,12(4):633-636
Based on the lead molecule FAUC 113, a series of di- and trisubstituted pyrazolo[1,5-a]pyridine derivatives was synthesized and investigated for their dopamine receptor binding profile. The carbonitrile 11a (FAUC 327) showed excellent pharmacological properties combining high D4 affinity (K(i)=1.5 nM) and selectivity with significant intrinsic activity (31%) in low nanomolar concentrations (EC50=1.5 nM). 相似文献
5.
Shaaban MR Saleh TS Mayhoub AS Mansour A Farag AM 《Bioorganic & medicinal chemistry》2008,16(12):6344-6352
A series of pyrazolo[1,5-a]pyrimidine, triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazole ring systems incorporating phenylsulfonyl moiety were synthesized via the reaction of 3-(N,N-dimethylamino)-1-aryl-2-(phenylsulfonyl)prop-2-en-1-one derivatives 2a,b with appropriate nitrogen nucleophiles. The analgesic and anti-inflammatory activities of the newly synthesized compound were investigated in vivo. 3-Bromo-2-phenyl-6-(phenylsulfonyl)-7-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (5e) was found to have an excellent analgesic activity in comparison with indomethacin as a reference drug, while the highest anti-inflammatory effect was observed in the case of 2-(4-bromophenyl)-6-(phenylsulfonyl)-5-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (5d). From the structure-activity relationship (SAR) point of view, the analgesic/anti-inflammatory activity of pyrazolo[1,5-a]pyrimidine derivatives was found to be much higher than triazolo[1,5-a]pyrimidine and pyrimido[1,2-a]benzimidazole derivatives. 相似文献
6.
Kato N Oka M Murase T Yoshida M Sakairi M Yamashita S Yasuda Y Yoshikawa A Hayashi Y Makino M Takeda M Mirensha Y Kakigami T 《Bioorganic & medicinal chemistry》2011,19(23):7221-7227
In the course of our program for discovery of novel DPP-IV inhibitors, a series of pyrazolo[1,5-a]pyrimidines were found to be novel DPP-IV inhibitors. We identified N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (4a) and described its pharmacological profiles. 相似文献
7.
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
8.
Allen SH Johns BA Gudmundsson KS Freeman GA Boyd FL Sexton CH Selleseth DW Creech KL Moniri KR 《Bioorganic & medicinal chemistry》2006,14(4):944-954
A novel series of potent C-6 substituted pyrazolo[1,5-a]pyridine inhibitors of herpes simplex viruses has been identified. A synthetic methodology was developed involving functionalization of a C-6 trifluoromethyl pyrazolo[1,5-a]pyridine to allow facile access to a diverse set of analogues from common late stage intermediates. The expansion of the SAR of this series at the 6 position allows for modifications to developability parameters such as clogP, while maintaining potency comparable to acyclovir. 相似文献
9.
Ivachtchenko AV Golovina ES Kadieva MG Kysil VM Mitkin OD Vorobiev AA Okun I 《Bioorganic & medicinal chemistry letters》2012,22(13):4273-4280
Synthesis and biological evaluation of a new series of structurally unrestricted and intramolecular hydrogen bond restricted derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines (angular tricyclics) and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines (linear tricyclics) are described. Structurally restricted derivatives are highly potent and selective blockers of 5-HT(6) receptors with little difference between angular or linear shape of the tricyclic core, the angular species being only slightly more potent. The angular representative of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines, 5, can be considered as more favorable candidate for further development as it shows only weak 5-HT(2B) blocking activity (IC(50)=6.16 μM as compared with IC(50)=1.8 nM for 5-HT(6) receptors) and very low hERG potassium channel blocking potency (IC(50)=54.2 μM). The linear analog, 11, is less favorable as while showing no binding to the 5-HT(2B) receptor at concentrations of up to 10 μM, it exhibits quite a high potency to block the hERG channel (IC(50)=0.5 μM). 相似文献
10.
Kendall JD O'Connor PD Marshall AJ Frédérick R Marshall ES Lill CL Lee WJ Kolekar S Chao M Malik A Yu S Chaussade C Buchanan C Rewcastle GW Baguley BC Flanagan JU Jamieson SM Denny WA Shepherd PR 《Bioorganic & medicinal chemistry》2012,20(1):69-85
We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model. 相似文献
11.
Gopalsamy A Yang H Ellingboe JW Tsou HR Zhang N Honores E Powell D Miranda M McGinnis JP Rabindran SK 《Bioorganic & medicinal chemistry letters》2005,15(6):1591-1594
A novel series of p21 chemoselective agents containing a pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides were identified by high throughput screening. Optimization of the amide region by parallel synthesis and the iterative design toward understanding structure-activity relationship to improve potency are described. The isopropyl carbamate derivative 34 was identified as a highly chemoselective agent displaying a potency of 51 nM in the p21 deficient cell line. 相似文献
12.
Baraldi PG Saponaro G Aghazadeh Tabrizi M Baraldi S Romagnoli R Moorman AR Varani K Borea PA Preti D 《Bioorganic & medicinal chemistry》2012,20(2):1046-1059
The discovery and development of adenosine receptor antagonists have represented for years an attractive field of research from the perspective of identifying new drugs for the treatment of widespread disorders such as inflammation, asthma and Parkinson's disease. The present work can be considered as an extension of our structure-activity relationship studies on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) nucleus, extensively investigated by us as a useful template, in particular, for the identification of A(2A) and A(3) adenosine receptor antagonists. In order to explore the role of the nitrogen at the 7-position, we performed a new synthetic strategy for the preparation of pyrrolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives which can be considered as 7-deaza analogues of the parent PTPs. We also synthesised a novel series of pyrazolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as junction isomers of the reference compounds. In both cases we obtained some examples of potent antagonists (K(i) in the low nanomolar range) with variable selectivity profiles in relation to the nature of substituents introduced at the C(5)-, N(8)- and/or N(9)-positions. The pyrrolo-triazolo-pyrimidine derivative 9b appeared to be a potent A(3) adenosine receptor antagonist (K(i)=10 nM) with good selectivity over hA(1) (74-fold) and hA(2A) (20-fold) adenosine receptors combined with low activity at the hA(2B) subtype (IC(50)=906 nM). Moreover, some examples of high-affinity A(1)/A(2A) dual antagonists have been identified in both series. This work constitutes a new and important contribution for the comprehension of the interaction between PTPs and adenosine receptors. 相似文献
13.
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
14.
A first microwave-assisted synthesis of a new class of novel purine thioglycoside analogues from readily available starting materials has been described. The key step of this protocol is the formation of sodium pyrazolo[1,5-a][1,3,5]triazine-4-thiolates via condensation of 5-amino-1H-pyrazoles with sodium cyanocarbonimidodithioate salt under microwave irradiation, followed by coupling with halo sugars to give the corresponding purine thioglycoside analogues. Further studies on the application of this method for the synthesis of other highly functionalized biologically active glycosides are underway. 相似文献
15.
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
16.
Golankiewicz B Januszczyk P Zeidler J Popenda M 《Nucleosides, nucleotides & nucleic acids》2004,23(1-2):127-136
Two new types of imidazole derivatives: N-(2-R1-5-R2-1H-imidazol-4-yl) thioureas 7a-g and N-(2-R1-5-R2-1H-imidazol-4-yl) formamides 8b,c,g were obtained in high yields by the hydrolytic degradation of 6-R1-8-R2-2-thioxo-2,3-dihydroimidazo[1,5-a]-1,3,5-triazin-4(1H)-ones 5a-g and 6-R1-8-R2-imidazo[1,5-a]-1,3,5-triazin-4(3H)-ones 6b,c,d, respectively. The tautomeric preferences of the new imidazoles were determined. 相似文献
17.
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
18.
Engler TA Malhotra S Burkholder TP Henry JR Mendel D Porter WJ Furness K Diefenbacher C Marquart A Reel JK Li Y Clayton J Cunningham B McLean J O'toole JC Brozinick J Hawkins E Misener E Briere D Brier RA Wagner JR Campbell RM Anderson BD Vaughn R Bennett DB Meier TI Cook JA 《Bioorganic & medicinal chemistry letters》2005,15(4):899-903
Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC(50)), although few show significant selectivity (>100x) versus CDK2, CDK4, or PKCbetaII. However, combining 3-(imidazo[1,2-a]pyridin-3-yl), 3-(pyrazolo[1,5-a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (=5 nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCbetaII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat). 相似文献
19.
Gabriella Guerrini Giovanna Ciciani Samuele Ciattini Letizia Crocetti Simona Daniele Claudia Martini 《Journal of enzyme inhibition and medicinal chemistry》2016,31(2):195-204
To investigate the binding affinity of GABAA receptor subtype, new pyrazolo [1,5-a]quinazolines were designed, synthesized, and in vitro evaluated. These compounds, 5-deaza analogues of pyrazolo[5,1-c][1,2,4]benzotriazine derivatives which were already studied in our research group, permit us to evaluate the relevance of the nitrogen or the oxygen atom at 5-position of the tricyclic scaffold. Molecular dynamic study was done on a set of the new and known ligands to rationalize and to explain the lack of affinity on the 4- or 5-substituted new derivative. In fact, from biological results, it can be found that the only 5-unsubstituted new derivative, compound 15, has receptor recognition (Ki?=?834.7?nM). 相似文献
20.
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