共查询到20条相似文献,搜索用时 15 毫秒
1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
Wu SC Yoon D Chin J van Kirk K Seethala R Golla R He B Harrity T Kunselman LK Morgan NN Ponticiello RP Taylor JR Zebo R Harper TW Li W Wang M Zhang L Sleczka BG Nayeem A Sheriff S Camac DM Morin PE Everlof JG Li YX Ferraro CA Kieltyka K Shou W Vath MB Zvyaga TA Gordon DA Robl JA 《Bioorganic & medicinal chemistry letters》2011,21(22):6693-6698
Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11β-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2014,24(21):5045-5049
A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11β-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability. 相似文献
9.
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
10.
Se Hoan Kim Ravirala Ramu Sung Wook Kwon Su-Hee Lee Chi Hyun Kim Seung Kyu Kang Sang Dal Rhee Myung Ae Bae Sung Hoon Ahn Duck Chan Ha Hyae Gyeong Cheon Ki Young Kim Jin Hee Ahn 《Bioorganic & medicinal chemistry letters》2010,20(3):1065-1069
A new series of cyclic sulfonamide derivatives was synthesized and evaluated for their ability to inhibit 11β-HSD1. Cyclic sulfonamides with phenylacetyl substituents at the 2-position showed nanomolar inhibitory activities. Among them, compound 4e exhibited a good in vitro inhibitory activity and selectivity toward human 11β-HSD2. 相似文献
11.
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
12.
James S. Scott Adrian L. Gill Linda Godfrey Sam D. Groombridge Amanda Rees John Revill Paul Schofield Pernilla Sörme Andrew Stocker John G. Swales Paul R.O. Whittamore 《Bioorganic & medicinal chemistry letters》2012,22(21):6756-6761
11β-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11β-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2014,24(12):2707-2711
Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11βHSD1. 相似文献
14.
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
15.
Xia G Xue M Liu L Yu J Liu H Li P Wang J Li Y Xiong B Shen J 《Bioorganic & medicinal chemistry letters》2011,21(19):5739-5744
Several potent and novel 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors were discovered from in silico screening the commercially available Maybridge database. Among them, seven hit compounds showed good affinity, with IC(50) values lower than 100 nM and the best one 3.7 nM. To select the lead for further optimization, computational ADME/T prediction, the CYP3A4 inhibition and 11β-HSD1 over 11β-HSD2 selectivity test were also performed. Taking all of the above factors into consideration, two promising compounds were selected as lead structures for further development. The employed hierarchical virtual screening protocol not only demonstrates its efficiency, but also provides novel and selective compounds for developing 11β-HSD1 inhibitors to protect against metabolic syndrome. 相似文献
16.
《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
17.
Yang-liang Ye Zhou Zhou Han-jun Zou Yu Shen Ti-fei Xu Jing Tang Hua-zhong Yin Min-li Chen Ying Leng Jian-hua Shen 《Bioorganic & medicinal chemistry》2009,17(15):5722-5732
PPARγ and 11β-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARγ agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11β-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of α-aryloxy-α-methylhydrocinnamic acids as dual functional agents which activate PPARγ and inhibit 11β-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARγ (EC50 = 6.76 μM) and 11β-HSD1 (IC50 = 0.76 μM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile. 相似文献
18.
《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
19.
Yusuke Oka Tetsuya Yabuuchi Yasuyuki Fujii Hidenori Ohtake Shunichi Wakahara Kayo Matsumoto Mayumi Endo Yunoshin Tamura Yoshinori Sekiguchi 《Bioorganic & medicinal chemistry letters》2012,22(24):7534-7538
A novel series of 2-aminothiazole-oxazoles was designed and synthesized as part of efforts to develop potent phosphoinositide 3-kinase γ (PI3Kγ) inhibitors. The modification of a high-throughput screening hit, compound 1, resulted in the identification of compounds 10 and 15, which displayed potent inhibitory activities in enzyme-based and cell-based assays. 相似文献
20.
Communicated by Ramaswamy H. Sarma 相似文献