共查询到20条相似文献,搜索用时 9 毫秒
1.
Dustin L. McMinn Yosup Rew Athena Sudom Seb Caille Michael DeGraffenreid Xiao He Randall Hungate Ben Jiang Juan Jaen Lisa D. Julian Jacob Kaizerman Perry Novak Daqing Sun Hua Tu Stefania Ursu Nigel P.C. Walker Xuelei Yan Qiuping Ye Zhulun Wang Jay P. Powers 《Bioorganic & medicinal chemistry letters》2009,19(5):1446-1450
Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11β-HSD1 in a rat pharmacodynamic model (ED50 = 10 mg/kg). 相似文献
2.
Rew Y DeGraffenreid M He X Jaen JC McMinn DL Sun D Tu H Ursu S Powers JP 《Bioorganic & medicinal chemistry letters》2012,22(11):3786-3790
A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively). 相似文献
3.
Ye XY Chen SY Nayeem A Golla R Seethala R Wang M Harper T Sleczka BG Li YX He B Kirby M Gordon DA Robl JA 《Bioorganic & medicinal chemistry letters》2011,21(22):6699-6704
Starting from high throughput screening hit 2-adamantyl acetic acid 3, a series of polycyclic acids have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD-1. Structure-activity relationships of two different regions of the chemotype (polycyclic ring and substituents on quaternary carbon) are discussed. 相似文献
4.
Unmesh Shah Craig D. Boyle Samuel Chackalamannil Hana Baker Timothy Kowalski Julie Lee Giuseppe Terracina Lili Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1551-1554
Inhibition of 11β-HSD1 has demonstrated potential in the treatment of various components of metabolic syndrome. We wish to report herein the discovery of novel azabicyclic sulfonamide based 11β-HSD1 inhibitors. Highly potent compounds exhibiting inhibitory activities at both human and mouse 11β-HSD1 were identified. Several compounds demonstrated significant in vivo activity in the mouse cortisone challenge assay. 相似文献
5.
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
6.
Yosup Rew Dustin L. McMinn Zhulun Wang Xiao He Randall W. Hungate Juan C. Jaen Athena Sudom Daqing Sun Hua Tu Stefania Ursu Elisia Villemure Nigel P.C. Walker Xuelei Yan Qiuping Ye Jay P. Powers 《Bioorganic & medicinal chemistry letters》2009,19(6):1797-1801
Discovery and optimization of a piperidyl benzamide series of 11β-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives. 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.
Colin M. Tice Wei Zhao Paula M. Krosky Barbara A. Kruk Jennifer Berbaum Judith A. Johnson Yuri Bukhtiyarov Reshma Panemangalore Boyd B. Scott Yi Zhao Joseph G. Bruno Lamont Howard Jennifer Togias Yuan-Jie Ye Suresh B. Singh Brian M. McKeever Peter R. Lindblom Joan Guo Rong Guo Herbert Nar David A. Claremon 《Bioorganic & medicinal chemistry letters》2010,20(22):6725-6729
Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC50 of 15.2 nM against human 11β-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2020,30(1):126715
A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles. 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.
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
12.
《Bioorganic & medicinal chemistry》2014,22(13):3441-3448
A series of 6-chloro-3-oxindole derivatives 1–25 were synthesized in high yields by the reaction of 6-chlorooxindole with different aromatic aldehydes in the presence of piperidine. All the synthesized compounds were isolated with E configuration. The structures were confirmed using spectroscopic techniques, including 1H NMR and EIMS. These compounds showed varying degree of yeast α-glucosidase inhibition and seven were found as potent inhibitors of the enzyme. Compounds 2, 3, 4, 5, 6, 23, and 25 exhibited IC50 values 2.71 ± 0.007, 11.41 ± 0.005, 37.93 ± 0.002, 15.19 ± 0.004, 24.71 ± 0.007, 17.33 ± 0.001, and 14.2 ± 0.002 μM, respectively, as compared to standard acarbose (IC50, 38.25 ± 0.12 μM). Docking studies helped to find interactions between the enzyme and the active compounds. As a result of this study, oxindoles have been discovered as a new class of α-glucosidase inhibitors which have not been reported earlier. 相似文献
13.
Adeniji AO Twenter BM Byrns MC Jin Y Winkler JD Penning TM 《Bioorganic & medicinal chemistry letters》2011,21(5):1464-1468
Aldo-keto reductase 1C3 (AKR1C3) also known as type 5 17β-hydroxysteroid dehydrogenase has been implicated as one of the key enzymes driving the elevated intratumoral androgen levels observed in castrate resistant prostate cancer (CRPC). AKR1C3 inhibition therefore presents a rational approach to managing CRPC. Inhibitors should be selective for AKR1C3 over other AKR1C enzymes involved in androgen metabolism. We have synthesized 2-, 3-, and 4-(phenylamino)benzoic acids and identified 3-(phenylamino)benzoic acids that have nanomolar affinity and exhibit over 200-fold selectivity for AKR1C3 versus other AKR1C isoforms. The AKR1C3 inhibitory potency of the 4′-substituted 3-(phenylamino)benzoic acids shows a linear correlation with both electronic effects of substituents and the pKa of the carboxylic acid and secondary amine groups, which are interdependent. These compounds may be useful in treatment and/or prevention of CRPC as well as understanding the role of AKR1C3 in endocrinology. 相似文献
14.
Wang T Block MA Cowen S Davies AM Devereaux E Gingipalli L Johannes J Larsen NA Su Q Tucker JA Whitston D Wu J Zhang HJ Zinda M Chuaqui C 《Bioorganic & medicinal chemistry letters》2012,22(5):2063-2069
The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε. 相似文献
15.
Ina Terstiege Matthew Perry Jens Petersen Christian Tyrchan Tor Svensson Helena Lindmark Linda Öster 《Bioorganic & medicinal chemistry letters》2017,27(3):679-687
A novel class of potent PI3Kδ inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kα program, turned moderately selective PI3Kδ compounds into highly potent and selective PI3Kδ inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kδ IC50 ? 1 nM in the enzyme assay, some of the most selective PI3Kδ inhibitors published to date, with a cell potency in a JeKo-cell assay of 20–120 nM. 相似文献
16.
Michael S. Malamas Keith Barnes Matthew Johnson Yu Hui Ping Zhou Jim Turner Yun Hu Erik Wagner Kristi Fan Rajiv Chopra Andrea Olland Jonathan Bard Menelas Pangalos Peter Reinhart Albert J. Robichaud 《Bioorganic & medicinal chemistry》2010,18(2):630-639
The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as β-secretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cell-based (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500×) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin.Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2′ pocket (BACE1 Pro70 changed to BACE2 Lys86) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand’s affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC50 value for BACE1 of 10 nM, and exhibited cellular activity with an EC50 value of 130 nM in the ELISA assay. 相似文献
17.
《Bioorganic & medicinal chemistry》2016,24(11):2466-2475
A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-θ (PKCθ) inhibitor. Using the docking model of compound 1 bound to PKCθ as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic substituent boosted PKCθ inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKCθ confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse. 相似文献
18.
Michael S. Malamas Keith Barnes Yu Hui Matthew Johnson Frank Lovering Jeff Condon William Fobare William Solvibile Jim Turner Yun Hu Eric S. Manas Kristi Fan Andrea Olland Rajiv Chopra Jonathan Bard Menelas N. Pangalos Peter Reinhart Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2010,20(7):2068-2073
The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer’s disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood–brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network. 相似文献
19.
Xiaocong M. Ye Andrei W. Konradi Minghua Sun Shendong Yuan Danielle L. Aubele Michael Dappen Darren Dressen Albert W. Garofalo Jacek J. Jagodzinski Lee Latimer Gary D. Probst Hing L. Sham David Wone Ying-zi Xu Daniel Ness Elizabeth Brigham Grace T. Kwong Chris Willtis Guriqbal S. Basi 《Bioorganic & medicinal chemistry letters》2013,23(4):996-1000
Structure–activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted. 相似文献
20.
Wang H Robl JA Hamann LG Simpkins L Golla R Li YX Seethala R Zvyaga T Gordon DA Li JJ 《Bioorganic & medicinal chemistry letters》2011,21(14):4146-4149
A series of pyridyl amide/sulfonamide inhibitors of 11β-HSD-1 were modified to incorporate a novel 1,2,4-triazolopyridine scaffold. Optimization of substituents at the 3 and 8 position of the TZP core, with a special focus on enhancing metabolic stability, resulted in the identification of compound 38 as a potent and metabolically stable inhibitor of the enzyme. 相似文献