共查询到20条相似文献,搜索用时 31 毫秒
1.
Tara R. Rheault Thomas R. Caferro Scott H. Dickerson Kelly H. Donaldson Michael D. Gaul Aaron S. Goetz Robert J. Mullin Octerloney B. McDonald Kimberly G. Petrov David W. Rusnak Lisa M. Shewchuk Glenn M. Spehar Anne T. Truesdale Dana E. Vanderwall Edgar R. Wood David E. Uehling 《Bioorganic & medicinal chemistry letters》2009,19(3):817-820
Two new series of potent and selective dual EGFR/ErbB-2 kinase inhibitors derived from novel thienopyrimidine cores have been identified. Isomeric thienopyrimidine cores were evaluated as isosteres for a 4-anilinoquinazoline core and several analogs containing the thieno[3,2-d]pyrimidine core showed anti-proliferative activity with IC50 values less than 1 μM against human tumor cells in vitro. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2014,24(17):4281-4285
A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R1 and R2 substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test. 相似文献
3.
McClellan WJ Dai Y Abad-Zapatero C Albert DH Bouska JJ Glaser KB Magoc TJ Marcotte PA Osterling DJ Stewart KD Davidsen SK Michaelides MR 《Bioorganic & medicinal chemistry letters》2011,21(18):5620-5624
In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors. 相似文献
4.
Takehiko Iwaki Yuji Nakamura Taisaku Tanaka Yasuyuki Ogawa Osamu Iwamoto Yoshihiko Okamura Yumi Kawase Mayumi Furuya Yoshiaki Oyama Takahiro Nagayama 《Bioorganic & medicinal chemistry letters》2017,27(21):4904-4907
Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC50 value of 0.073 μM, indicating 350-fold potency compared to the hit compound 3. 相似文献
5.
Timothy P. Heffron Megan Berry Georgette Castanedo Christine Chang Irina Chuckowree Jennafer Dotson Adrian Folkes Janet Gunzner John D. Lesnick Cristina Lewis Simon Mathieu Jim Nonomiya Alan Olivero Jodie Pang David Peterson Laurent Salphati Deepak Sampath Steve Sideris Daniel P. Sutherlin Vickie Tsui Bing-yan Zhu 《Bioorganic & medicinal chemistry letters》2010,20(8):2408-2411
Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor. 相似文献
6.
Richard W.A. Luke Peter Ballard David Buttar Leonie Campbell Jon Curwen Steve C. Emery Alison M. Griffen Lorraine Hassall Barry R. Hayter Cliff D. Jones William McCoull Martine Mellor Mike L. Swain Julie A. Tucker 《Bioorganic & medicinal chemistry letters》2009,19(23):6670-6674
The SAR and improvement in potency against Tie2 of novel thienopyrimidine and thiazolopyrimidine kinase inhibitors are reported. The crystal structure of one of these compounds bound to the Tie-2 kinase domain is consistent with the SAR. These compounds have moderate potency in cellular assays of Tie-2 inhibition, good physical properties, DMPK, and show evidence of in vivo inhibition of Tie-2. 相似文献
7.
Alex G. Waterson Kimberly G. Petrov Keith R. Hornberger Robert D. Hubbard Douglas M. Sammond Stephon C. Smith Hamilton D. Dickson Thomas R. Caferro Kevin W. Hinkle Kirk L. Stevens Scott H. Dickerson David W. Rusnak Glenn M. Spehar Edgar R. Wood Robert J. Griffin David E. Uehling 《Bioorganic & medicinal chemistry letters》2009,19(5):1332-1336
Aniline ‘headgroups’ were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline. 相似文献
8.
Steven W. Kortum Rhonda M. Lachance Barbara A. Schweitzer Gopichand Yalamanchili Hayat Rahman Michael D. Ennis Rita M. Huff Ruth E. TenBrink 《Bioorganic & medicinal chemistry letters》2009,19(20):5919-5923
Herein we describe the design and synthesis of a novel series of potent thienopyrimidine P2Y12 inhibitors and the negative impact protein binding has on the inhibition of platelet aggregation. 相似文献
9.
Katada J Iijima K Muramatsu M Takami M Yasuda E Hayashi M Hattori M Hayashi Y 《Bioorganic & medicinal chemistry letters》1999,9(6):797-802
We synthesized a series of thienopyrimidine derivatives and examined their cytotoxic effects on several cell lines. One of the derivatives, NSL-1406, was shown to exert potent cytotoxic effects on leukemia cell line including P388 cells and J774 cells. It was also inhibitory on mouse osteoclasts and suppressed the in vitro bone resorption by osteoclasts at nanomolar concentrations. 相似文献
10.
Joshua Kaplan Jeroen C. Verheijen Natasja Brooijmans Lourdes Toral-Barza Irwin Hollander Ker Yu Arie Zask 《Bioorganic & medicinal chemistry letters》2010,20(2):640-643
The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors. 相似文献
11.
Xiaowen Wang Mingbo Su You Li Tongchao Liu Yujie Wang Yabing Chen Le Tang Yu-Peng He Xiaoguang Ding Fang Yu Jingkang Shen Jia Li Yubo Zhou Yue-Lei Chen Bing Xiong 《Bioorganic & medicinal chemistry letters》2019,29(6):844-847
Tranylcypromine moiety extracted from LSD1 inhibitors and 6-trifluoroethyl thienopyrimidine moiety from menin-MLL1 PPI inhibitors were merged to give new chemotypes for medicinal chemistry study. Among 15 new compounds prepared in this work, some exhibited nanomolar LSD1 activity and good selectivity over MAO-A/B, low micromolar menin-MLL1 PPI inhibitory activity, as well as submicromolar MV4-11 antiprofilative activities. Intracellular LSD1 engagement of compounds with higher enzymatic and antiproliferative activities was confirmed by CD86 mRNA up-regulation experiments. 相似文献
12.
An important role in functioning of reproductive tissues is played by signaling systems that are regulated by luteinizing hormone (LH) and human chorionic gonadotropin (hCG) that include LH receptors as sensor components. Use of LH and hCG in medicine for treatment of diseases of the reproductive system and for solution of tasks of auxiliary reproductive technologies is restricted by their high cost, the necessity of parenteral introduction, and the presence of side effects. However, in the last few years, low molecular weight agonists of LH receptor have been developed that are devoid of these shortcomings and can be administered perorally. The most effective of them are thienopyrimidine derivatives, in particular the Org 43553 compound. The goal of this work was to study the effect of newly synthesized analogs of Org 43553, 5-amino-N-(tert-butyl)-4-(3-(isonicotinamide)phenyl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxamide (compound 1) and 5-amino-N-(tert-butyl)-2-(methylthio)-4-(3-(thiophene-3-carboxamido)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 2), on the basal and LH-stimulated adenylyl cyclase (AC) activity in the plasma-membrane fractions isolated from testes and ovaries of rats. Compounds 1 and 2 have been shown to stimulate in a dose-dependent manner the basal AC activity in the membranes isolated from the testes and ovaries, compound 2 being more effective as compared with compound 1. The EC50 values for compounds 1 and 2 on AC activity were 1.05–1.12 and 0.28–0.37 μM, respectively. The stimulating effect of hCG on AC activity was retained in the presence of the thienopyrimidine derivatives, while at low, nonsaturating hormone concentrations, the additivity of the effects of hCG and of compounds 1 and 2 on the AC activity was observed. This indicates that the thienopyrimidine derivatives interact with the allosteric site located in the LH receptor transmembrane channel and does not overlap with the binding site of gonadotropins located in the N-terminal ectodomain. The action of compounds 1 and 2 was tissue-specific and not found in tissues with no LH receptors present. Our obtained data indicate that compounds 1 and 2 may become prototypes for creation of drugs that are regulators of functions of the male and female reproductive systems. 相似文献
13.
SP Hollinshead PC Astles MG Chambers MP Johnson J Palmer MW Tidwell 《Bioorganic & medicinal chemistry letters》2012,22(15):4962-4966
A focused screening strategy identified thienopyrimidine 1 as a hCB2 cannabinoid receptor agonist with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a less lipophilic purine core. Examples from this novel series were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1. Compound 10 possesses good biopharmaceutical properties, is highly water soluble and demonstrates robust oral activity in rodent models of joint pain. 相似文献
14.
Yoon Kyung Jang Kyu Myung Lee Kwan-Young Jung Seung Kyu Kang Suvarna H. Pagire Jun Mi Lee Haushabhau S. Pagire Kwang Rok Kim Myung Ae Bae Hohjai Lee Sang Dal Rhee Jin Hee Ahn 《Bioorganic & medicinal chemistry letters》2017,27(16):3909-3914
A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists. Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119 agonistic activities. Among them, compound 9c displayed good in vitro activity and potency. Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and increased GLP-1 secretion in intestinal cells. 相似文献
15.
Hongwang Zhang Longhu Zhou Sarah Amichai Keivan Zandi Bryan Cox Raymond Schinazi Franck Amblard 《Bioorganic & medicinal chemistry letters》2019,29(20):126639
Exploration of the chemical space of known influenza polymerase PB2 inhibitor Pimodivir, was performed by our group. We synthesized and identified compounds 16a and 16b, two novel thienopyrimidine derivatives displaying anti-influenza A activity in the single digit nanomolar range in cell culture. Binding of these unique compounds in the influenza polymerase PB2 pocket was also determined using molecular modeling. 相似文献
16.
Modica M Romeo G Materia L Russo F Cagnotto A Mennini T Gáspár R Falkay G Fülöp F 《Bioorganic & medicinal chemistry》2004,12(14):3891-3901
This work reports on the synthesis and affinities for the 5-HT(3) versus the 5-HT(4) receptor of new piperazinyl-substituted thienopyrimidine derivatives 20-45 with a view to identify potent and selective ligands for the 5-HT(3) receptor. Some of the new compounds show good affinity for the 5-HT(3) receptor and, notably, do not display any affinity for the 5-HT(4) receptor. 4-(4-Methyl-1-piperazinyl)-2-methylthio-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine 31 exhibits the highest affinity for the 5-HT(3) receptor (Ki = 33 nM) and behaves as noncompetitive antagonist. 相似文献
17.
Ariamala Gopalsamy Mengxiao Shi Yongbo Hu Frederick Lee Larry Feldberg Eileen Frommer Steven Kim Karen Collins Donald Wojciechowicz Robert Mallon 《Bioorganic & medicinal chemistry letters》2010,20(8):2431-2434
In continuation of our efforts toward hit identification and optimization for a B-Raf kinase project, we have employed a scaffold hopping strategy. The original HTS hit scaffold pyrazolo[1,5-a]pyrimidine was replaced with different thienopyrimidine and thienopyridine scaffolds to append the optimal pharmacophore moieties in order to generate novel B-raf kinase inhibitors with desirable potency and properties. This strategy led to the identification of additional lead compound 11b which had good enzyme and cell potency, while maintaining selectivity over a number of kinases. 相似文献
18.
Stefan Tasler Roland Baumgartner Astrid Ammendola Josef Schachtner Tanja Wieber Marcus Blisse Sandra Rath Mirko Zaja Philipp Klahn Udo Quotschalla Peter Ney 《Bioorganic & medicinal chemistry letters》2010,20(20):6108-6115
Resulting from a vHTS based on a pharmacophore alignment on known β3-adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human β3-AR agonist, yielding a lead compound with an excellent cellular activity of EC50 = 20 pM, selectivity over hβ1- and hβ2-adrenoceptors and a promising safety profile. 相似文献
19.
Songwen Lin Chunyang Wang Ming Ji Deyu Wu Yuanhao Lv Li Sheng Fangbin Han Yi Dong Kehui Zhang Yakun Yang Yan Li Xiaoguang Chen Heng Xu 《Bioorganic & medicinal chemistry》2018,26(3):637-646
A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile. 相似文献
20.
Reham R. Khattab Asma K. Alshamari Allam A. Hassan Hussein H. Elganzory Wael A. El-Sayed Hanem M. Awad Eman S. Nossier Nasser A. Hassan 《Journal of enzyme inhibition and medicinal chemistry》2021,36(1):504
In the current study, new thienopyrimidine conjugates bearing 1,2,3-triazole core and different sugar moieties have been designed and synthesized by Cu(I)-catalysed click dipolar cycloaddition. The cytotoxic activity of the synthesised conjugates 2, 5, 7, and 13–18 was studied against HCT-116 and MCF-7 cell lines by the MTT assay. The triazole glycosides 16 and 18 provided significant cytotoxic activities against HCT-116 cell lines comparable to that of doxorubicin and other studied compounds. The cytotoxic behaviour against MCF-7 exhibited that all the investigated compounds were more potent than doxorubicin. Moreover, all screened targets were evaluated against mutant EGFR kinase type L858R and the results revealed that the acetylated 1,2,3-triazole glycosides 13–18 exhibited excellent EGFR inhibitory activity in comparison with gefitinib. Furthermore, molecular modelling studies were performed to investigate the binding affinity of the most active compounds to EGFR enzyme. 相似文献