共查询到20条相似文献,搜索用时 31 毫秒
1.
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is a potential target for treatment of diabetes and metabolic syndrome. Docking and pharmacophore modeling have been used to discover novel inhibitors of 11beta-HSD1. Several compounds, with large structural diversity and good potency against 11beta-HSD1, have been found and their potency was determined by the enzyme assay. New scaffolds of 11beta-HSD1 inhibitors are also reported. 相似文献
2.
Xiang J Ipek M Suri V Massefski W Pan N Ge Y Tam M Xing Y Tobin JF Xu X Tam S 《Bioorganic & medicinal chemistry letters》2005,15(11):2865-2869
The design, synthesis, and biological evaluation of arylsulfonamidooxazoles as 11beta-HSD1 inhibitors and the serendipitous discovery of beta-keto sulfones as potent 11beta-HSD1 inhibitors are described here. These two classes of compounds are not active against 11beta-HSD2 and therefore may have significant therapeutic potential for metabolic syndrome, type 2 diabetes and related metabolic dysfunctions. 相似文献
3.
David R. Bauman Alan Whitehead Lisa C. Contino Jisong Cui Margarita Garcia-Calvo Xin Gu Nancy Kevin Xiuying Ma Lee-yuh Pai Kashmira Shah Xiaolan Shen Sloan Stribling Hratch J. Zokian Joe Metzger Diane E. Shevell Sherman T. Waddell 《Bioorganic & medicinal chemistry letters》2013,23(12):3650-3653
In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11β-HSD1 inhibitors, we examined a set of 11β-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11β-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11β-HSD1 independent pathway. 相似文献
4.
Webster SP Ward P Binnie M Craigie E McConnell KM Sooy K Vinter A Seckl JR Walker BR 《Bioorganic & medicinal chemistry letters》2007,17(10):2838-2843
A series of adamantyl amide 11beta-HSD1 inhibitors has been discovered and chemically modified. Selected compounds are selective for 11beta-HSD1 over 11beta-HSD2 and possess excellent cellular potency in human and murine 11beta-HSD1 assays. Good pharmacodynamic characteristics are observed in ex vivo assays. 相似文献
5.
Head and neck squamous cell carcinomas (HNSCC) are at a high risk of recurrence and multimodal therapy have not significantly improved survival in recent decades. Although immune checkpoint inhibitors (ICIs) are effective in a small proportion of HNSCC patients, the majority do not respond. In this study, we for the first time revealed that xenobiotic metabolic process was significantly associated with resistance to programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors in HNSCC and found that ATP binding cassette subfamily B member 11 (ABCB11) accumulated in immature tertiary lymphoid structures (TLSs) predicted worse progression-free survival (PFS) and overall survival (OS) after PD-1/PD-L1 inhibitors therapy. Moreover, the expression of cytochrome P450 1A2 (CYP1A2), a cytochrome P450 (CYP) enzyme that participates in xenobiotic metabolic process, was significantly upregulated in CD45+ABCB11+ tumor-infiltrating lymphocytes (TILs) compared with CD45+ABCB11−TILs in HNSCC tissues. Whole slide scans of 110 HNSCC tissues with hematoxylin-eosin (HE) and multispectral immuno-fluorescent (mIF) staining revealed that ABCB11 had a high co-expression with CYP1A2 in immature TLSs, and colocalization of ABCB11 and CYP1A2 in immature TLs significantly associated with high infiltration of immunosuppressive T-regulatory (Treg). Our study revealed that ABCB11 accumulated in immature TLSs might upregulate CYP1A2 to mediate xenobiotic metabolic process, thus increase the immunosuppressive Treg infiltration, and induce resistance to PD-1/PD-L1 inhibitors in HNSCC. 相似文献
6.
Hakki T Hübel K Waldmann H Bernhardt R 《The Journal of steroid biochemistry and molecular biology》2011,125(1-2):120-128
Cytochrome P450 enzymes play an important role in steroid hormone biosynthesis of the human adrenal gland, e.g., the production of cortisol and aldosterone. Aldosterone, the most important human mineralocorticoid, is involved in the regulation of the salt and water homeostasis of the body and thus in the regulation of blood pressure, whereas cortisol is the most important glucocorticoid of the human body. CYP11B-dependent steroid hydroxylases are drug development targets, and since they are very closely related enzymes, the discovery of selective inhibitors has been subject to intense investigations for several years. Here we report the development of a whole-cell medium throughput screening technology for the discovery of CYP11B2 inhibitors. The new screening system displayed high reproducibility and was applied to investigate a library of pharmacologically active compounds. 1268 compounds were investigated during this study which revealed 5 selective inhibitors of CYP11B2 (after validation against CYP11B1). The new inhibitors of CYP11B2 are already existing drugs that could be used either in the treatment of hyperaldosteronism-related diseases or as lead compounds that could further be optimised to achieve safer and selective inhibitors of aldosterone synthase. Article from the Special issue on 'Targeted Inhibitors'. 相似文献
7.
Sutin L Andersson S Bergquist L Castro VM Danielsson E James S Henriksson M Johansson L Kaiser C Flyrén K Williams M 《Bioorganic & medicinal chemistry letters》2007,17(17):4837-4840
2,5,5-Trisubstituted oxazolones were identified as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The synthesis, structure-activity relationship and metabolic stability of these compounds are presented. 相似文献
8.
Flyrén K Bergquist LO Castro VM Fotsch C Johansson L St Jean DJ Sutin L Williams M 《Bioorganic & medicinal chemistry letters》2007,17(12):3421-3425
A series of piperidine amide inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) were identified via modifications of the HTS hit compound 1. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. 相似文献
9.
Sun D Wang Z Di Y Jaen JC Labelle M Ma J Miao S Sudom A Tang L Tomooka CS Tu H Ursu S Walker N Yan X Ye Q Powers JP 《Bioorganic & medicinal chemistry letters》2008,18(12):3513-3516
High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11beta-HSD1 IC(50)=3nM). 相似文献
10.
Daqing Sun Zhulun Wang Mario Cardozo Rebekah Choi Michael DeGraffenreid Yongmei Di Xiao He Juan C. Jaen Marc Labelle Jinsong Liu Ji Ma Shichang Miao Athena Sudom Liang Tang Hua Tu Stefania Ursu Nigel Walker Xuelei Yan Qiuping Ye Jay P. Powers 《Bioorganic & medicinal chemistry letters》2009,19(5):1522-1527
The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model. 相似文献
11.
Sun D Wang Z Caille S DeGraffenreid M Gonzalez-Lopez de Turiso F Hungate R Jaen JC Jiang B Julian LD Kelly R McMinn DL Kaizerman J Rew Y Sudom A Tu H Ursu S Walker N Willcockson M Yan X Ye Q Powers JP 《Bioorganic & medicinal chemistry letters》2011,21(1):405-410
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models. 相似文献
12.
Kratschmar DV Vuorinen A Da Cunha T Wolber G Classen-Houben D Doblhoff O Schuster D Odermatt A 《The Journal of steroid biochemistry and molecular biology》2011,125(1-2):129-142
Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18β-Glycyrrhetinic acid (GA), the biologically active triterpenoid metabolite of glycyrrhizin, which is contained in the roots and rhizomes of licorice (Glycyrrhiza spp.), represents a well-known but non-selective inhibitor of 11β-hydroxysteroid dehydrogenases (11β-HSDs). However, to assess the physiological functions of the respective enzymes and for potential therapeutic applications selective inhibitors are needed. In the present study, we applied bioassays and 3D-structure modeling to characterize nine 11β-HSD1 and fifteen 11β-HSD2 inhibiting GA derivatives. Comparison of the GA derivatives in assays using cell lysates revealed that modifications at the 3-hydroxyl and/or the carboxyl led to highly selective and potent 11β-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivatives as 11β-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11β-HSD2, despite significant species-specific differences. The selected GA derivatives potently inhibited 11β-HSD2 in intact SW-620 colon cancer cells, although the rank order of inhibitory potential differed from that obtained in cell lysates. The biological activity of compounds was further demonstrated in glucocorticoid receptor (GR) transactivation assays in cells coexpressing GR and 11β-HSD1 or 11β-HSD2. 3D-structure modeling provides an explanation for the differences in the selectivity and activity of the GA derivatives investigated. The most potent and selective 11β-HSD2 inhibitors should prove useful as mechanistic tools for further anti-inflammatory and anti-cancer in vitro and in vivo studies. Article from the Special issue on Targeted Inhibitors. 相似文献
13.
Venier O Pascal C Braun A Namane C Mougenot P Crespin O Pacquet F Mougenot C Monseau C Onofri B Dadji-Faïhun R Leger C Ben-Hassine M Van-Pham T Ragot JL Philippo C Güssregen S Engel C Farjot G Noah L Maniani K Nicolaï E 《Bioorganic & medicinal chemistry letters》2011,21(8):2244-2251
A High Throughput Screening campaign allowed the identification of a novel class of ureas as 11β-HSD1 inhibitors. Rational chemical optimization provided potent and selective inhibitors of both human and murine 11β-HSD1 with an appropriate ADME profile and ex vivo activity in target tissues. 相似文献
14.
Zhu Y Olson SH Hermanowski-Vosatka A Mundt S Shah K Springer M Thieringer R Wright S Xiao J Zokian H Balkovec JM 《Bioorganic & medicinal chemistry letters》2008,18(11):3405-3411
4-Methyl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They were active in vitro and in an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relationships are presented. 相似文献
15.
Don MJ Lewis DF Wang SY Tsai MW Ueng YF 《Bioorganic & medicinal chemistry letters》2003,13(15):2535-2538
Derivatives of a CYP1A2 inhibitor rutaecarpine were synthesized to have potent and selective inhibition of human CYP1 members. Structural modelling shows a good fitting of rutaecarpine with the putative active site of human CYP1A2. Among the derivatives, 10- and 11-methoxyrutaecarpine are the most selective CYP1B1 inhibitors. 1-Methoxyrutaecarpine and 1,2-dimethoxyrutaecarpine are the most selective CYP1A2 inhibitors. 相似文献
16.
Matsufuji T Ikeda M Naito A Hirouchi M Takakusa H Kanda S Izumi M Harada J Shinozuka T 《Bioorganic & medicinal chemistry letters》2012,22(15):5067-5070
The discovery, optimization and structure-activity relationship of novel FATP1 inhibitors have been described. The detailed SAR studies of each moiety of the inhibitors combined with metabolite analysis led to the identification of the potent inhibitors 11p and 11q with improved blood stability. 相似文献
17.
Aster SD Graham DW Kharbanda D Patel G Ponpipom M Santorelli GM Szymonifka MJ Mundt SS Shah K Springer MS Thieringer R Hermanowski-Vosatka A Wright SD Xiao J Zokian H Balkovec JM 《Bioorganic & medicinal chemistry letters》2008,18(9):2799-2804
3-Aryl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). They are active in both in vitro and an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relationships are presented. 相似文献
18.
Wang H Ruan Z Li JJ Simpkins LM Smirk RA Wu SC Hutchins RD Nirschl DS Van Kirk K Cooper CB Sutton JC Ma Z Golla R Seethala R Salyan ME Nayeem A Krystek SR Sheriff S Camac DM Morin PE Carpenter B Robl JA Zahler R Gordon DA Hamann LG 《Bioorganic & medicinal chemistry letters》2008,18(11):3168-3172
Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series. 相似文献
19.
Yan X Wang Z Sudom A Cardozo M DeGraffenreid M Di Y Fan P He X Jaen JC Labelle M Liu J Ma J McMinn D Miao S Sun D Tang L Tu H Ursu S Walker N Ye Q Powers JP 《Bioorganic & medicinal chemistry letters》2010,20(23):7071-7075
In this communication, human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11β-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model. 相似文献
20.
Zheng X Oda H Takamatsu K Sugimoto Y Tai A Akaho E Ali HI Oshiki T Kakuta H Sasaki K 《Bioorganic & medicinal chemistry》2007,15(2):1014-1021
In order to create novel analgesic agents without gastric disturbance, structurally simple cyclooxygenase-1 (COX-1) inhibitors with a benzenesulfonanilide skeleton were designed and synthesized. As a result, compounds 11f and 15a, which possess a p-amino group on the benzenesulfonyl moiety and p-chloro group on the anilino moiety, showed COX-1-selective inhibition. Moreover compound 11f, which is the most potent compound in this study showed more potent analgesic activity than that of aspirin at 30 mg/kg by po. The anti-inflammatory activity and gastric damage, however, were very weak or not detectably different from aspirin. Since the structure of our COX-1 inhibitors are very simple, they may be useful as lead compounds for superior COX-1 inhibitors as analgesic agents without gastric disturbance. 相似文献