共查询到20条相似文献,搜索用时 78 毫秒
1.
Sorensen B Winn M Rohde J Shuai Q Wang J Fung S Monzon K Chiou W Stolarik D Imade H Pan L Deng X Chovan L Longenecker K Judge R Qin W Brune M Camp H Frevert EU Jacobson P Link JT 《Bioorganic & medicinal chemistry letters》2007,17(2):527-532
Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing. 相似文献
2.
Olivier Venier Cécile Pascal Alain Braun Claudie Namane Patrick Mougenot Olivier Crespin François Pacquet Cécile Mougenot Catherine Monseau Bénédicte Onofri Rommel Dadji-Faïhun Céline Leger Majdi Ben-Hassine Thao Van-Pham Jean-Luc Ragot Christophe Philippo Géraldine Farjot Lionel Noah Antonio Castro 《Bioorganic & medicinal chemistry letters》2013,23(8):2414-2421
Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(2):654-660
A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11β-HSD1 enzyme. Optimization of two regions of A, R1 and R2 respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11β-HSD1 with a favorable development profile. 相似文献
4.
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
5.
Hengmiao Cheng Jacqui Hoffman Phuong Le Sajiv K. Nair Stephan Cripps Jean Matthews Christopher Smith Michele Yang Stan Kupchinsky Klaus Dress Martin Edwards Bridget Cole Evan Walters Christine Loh Jacques Ermolieff Andrea Fanjul Ganesh B. Bhat Jocelyn Herrera Tom Pauly Natilie Hosea Paul Rejto 《Bioorganic & medicinal chemistry letters》2010,20(9):2897-2902
The design and development of a series of highly selective pyrrolidine carboxamide 11β-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11β-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11β-HSD1 selective inhibitor 42. 相似文献
6.
Oh M Im I Lee YJ Kim YH Yoon JH Park HG Higashiyama S Kim YC Park WJ 《Bioorganic & medicinal chemistry letters》2004,14(24):6071-6074
We describe a series of potent and selective inhibitors of ADAM12 that were discovered using computational screening of a focused virtual library. The initial structure-based virtual screening selected 64 compounds from a 3D database of 67,062 molecules. Being evaluated by a cell-based ADAM12 activity assay, compounds 5, 11, 14, 16 were further identified as the potent and selective inhibitors of ADAM12 with low nanomolar IC50 values. The mechanism underlying the potency and selectivity of a representative compound, 5, was investigated through molecular docking studies. 相似文献
7.
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
8.
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
9.
Yeh VS Patel JR Yong H Kurukulasuriya R Fung S Monzon K Chiou W Wang J Stolarik D Imade H Beno D Brune M Jacobson P Sham H Link JT 《Bioorganic & medicinal chemistry letters》2006,16(20):5414-5419
A series of metabolically stable adamantane amide 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity and good pharmacokinetic and pharmacodynamic profiles. 相似文献
10.
Sun W Maletic M Mundt SS Shah K Zokian H Lyons K Waddell ST Balkovec J 《Bioorganic & medicinal chemistry letters》2011,21(7):2141-2145
3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD1). They were shown to be active in the mouse in vivo pharmacodynamic model (PD) for HSD1 but exhibited a potent off-target activation of the Pregnane X Receptor (PXR). SAR studies and synthesis of analogs that led to the discovery of a selective HSD1 inhibitor are described in detail. 相似文献
11.
Zhu GD Gandhi VB Gong J Luo Y Liu X Shi Y Guan R Magnone SR Klinghofer V Johnson EF Bouska J Shoemaker A Oleksijew A Jarvis K Park C Jong RD Oltersdorf T Li Q Rosenberg SH Giranda VL 《Bioorganic & medicinal chemistry letters》2006,16(13):3424-3429
We describe a series of potent and selective oxindole-pyridine-based protein kinase B/Akt inhibitors. The most potent compound 11n in this series demonstrated an IC(50) of 0.17nM against Akt1 and more than 100-fold selectivity over other Akt isozymes. The selectivity against other protein kinases was highly dependent on the C-3 substitutions at the oxindole scaffold, with unsubstituted 9e or 3-furan-2-ylmethylene (11n) more selective and 3-(1H-pyrrol-2-yl)methylene (11f) or 3-(1H-imidazol-2-yl)methylene (11k) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity. 相似文献
12.
Hu Q Negri M Jahn-Hoffmann K Zhuang Y Olgen S Bartels M Müller-Vieira U Lauterbach T Hartmann RW 《Bioorganic & medicinal chemistry》2008,16(16):7715-7727
Thirty-five novel substituted imidazolyl methylene biphenyls have been synthesized as CYP17 inhibitors for the potential treatment of prostate cancer. Their activities have been tested with recombinant human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against CYP11B1, CYP11B2, and hepatic CYP enzymes 3A4, 1A2, 2B6 and 2D6. The core rigidified compounds (30-35) were the most active ones, being much more potent than Ketoconazole and reaching the activity of Abiraterone. However, they were not very selective. Another rather potent and more selective inhibitor (compound 23, IC(50)=345 nM) was further examined in rats regarding plasma testosterone levels and pharmacokinetic properties. Compared to the reference Abiraterone, 23 was more active in vivo, showed a longer plasma half-life (10h) and a higher bioavailability. Using our CYP17 homology protein model, docking studies with selected compounds were performed to study possible interactions between inhibitors and amino acid residues of the active site. 相似文献
13.
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
14.
Patel JR Shuai Q Dinges J Winn M Pliushchev M Fung S Monzon K Chiou W Wang J Pan L Wagaw S Engstrom K Kerdesky FA Longenecker K Judge R Qin W Imade HM Stolarik D Beno DW Brune M Chovan LE Sham HL Jacobson P Link JT 《Bioorganic & medicinal chemistry letters》2007,17(3):750-755
A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed. 相似文献
15.
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
16.
Adamantyl groups are widely used in medicinal chemistry. However, metabolism limits their usage. Herein, we report the first systematic study of adamantyl ureas and diureas bearing substituents in bridgehead positions of adamantane and/or spacers between urea groups and adamantane group, and tested their effects on soluble epoxide hydrolase inhibitor potency and metabolic stability. Interestingly, the effect on activity against human and murine sEH varied in opposite ways with each new methyl group introduced into the molecule. Compounds with three methyl substituents in adamantane were very poor inhibitors of murine sEH while still very potent against human sEH. In addition, diureas with terminal groups bigger than sEH catalytic tunnel diameter were still good inhibitors suggesting that the active site of sEH opens to capture the substrate or inhibitor molecule. The introduction of one methyl group leads to 4-fold increase in potency without noticeable loss of metabolic stability compared to the unsubstituted adamantane. However, introduction of two or three methyl groups leads to 8-fold and 98-fold decrease in stability in human liver microsomes for the corresponding compounds. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(5):1421-1425
Many adamantane derivatives have been demonstrated to function as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. 3-Amino-N-adamantyl-3-methylbutanamide derivatives were optimized by structure-based drug design. Compound 8j exhibited a good in vitro and ex vivo inhibitory activity against both human and mouse 11β-HSD1. 相似文献
18.
Gu X Dragovic J Koo GC Koprak SL LeGrand C Mundt SS Shah K Springer MS Tan EY Thieringer R Hermanowski-Vosatka A Zokian HJ Balkovec JM Waddell ST 《Bioorganic & medicinal chemistry letters》2005,15(23):5266-5269
Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) inhibitors with excellent pharmacokinetic profiles. 相似文献
19.
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
20.
Brent R. Whitehead Michael M.-C. Lo Amjad Ali Min K. Park Scott B. Hoyt Yusheng Xiong Jiaqiang Cai Emma Carswell Andrew Cooke John MacLean Paul Ratcliffe John Robinson D. Jonathan Bennett Joseph A. Clemas Tom Wisniewski Mary Struthers Doris Cully Douglas J. MacNeil 《Bioorganic & medicinal chemistry letters》2017,27(2):143-146
The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1. 相似文献