共查询到20条相似文献,搜索用时 0 毫秒
1.
Peters JU Galley G Jacobsen H Czech C David-Pierson P Kitas EA Ozmen L 《Bioorganic & medicinal chemistry letters》2007,17(21):5918-5923
Structural modifications of the gamma-secretase inhibitor, LY411575, led to a malonamide analogue (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metabolically labile position provided an improved compound (R/S),(S)-13 with high in vitro activity (IC(50)=1.7 nM), and in vivo activity after oral administration (MED=3 mg/kg). Further modifications gave an equipotent carbamate analogue 14 with improved molecular properties. 相似文献
2.
Josien H Bara T Rajagopalan M Asberom T Clader JW Favreau L Greenlee WJ Hyde LA Nomeir AA Parker EM Pissarnitski DA Song L Wong GT Zhang L Zhang Q Zhao Z 《Bioorganic & medicinal chemistry letters》2007,17(19):5330-5335
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease. 相似文献
3.
Kreft A Harrison B Aschmies S Atchison K Casebier D Cole DC Diamantidis G Ellingboe J Hauze D Hu Y Huryn D Jin M Kubrak D Lu P Lundquist J Mann C Martone R Moore W Oganesian A Porte A Riddell DR Sonnenberg-Reines J Stock JR Sun SC Wagner E Woller K Xu Z Zhou H Steven Jacobsen J 《Bioorganic & medicinal chemistry letters》2008,18(14):4232-4236
Using a cell-based assay, we have identified a new series of Notch-sparing γ-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved γ-secretase inhibitory potency and Notch-sparing selectivity. 相似文献
4.
Churcher I Beher D Best JD Castro JL Clarke EE Gentry A Harrison T Hitzel L Kay E Kerrad S Lewis HD Morentin-Gutierrez P Mortishire-Smith R Oakley PJ Reilly M Shaw DE Shearman MS Teall MR Williams S Wrigley JD 《Bioorganic & medicinal chemistry letters》2006,16(2):280-284
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice). 相似文献
5.
Black WC Bayly CI Davis DE Desmarais S Falgueyret JP Léger S Li CS Massé F McKay DJ Palmer JT Percival MD Robichaud J Tsou N Zamboni R 《Bioorganic & medicinal chemistry letters》2005,15(21):4741-4744
The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins. 相似文献
6.
Li J Bertinato P Cheng H Cole BM Bronk BS Jaynes BH Hickman A Haven ML Kolosko NL Barry CJ Manion TB 《Bioorganic & medicinal chemistry letters》2006,16(11):3039-3042
We have successfully identified a number of novel MTP inhibitors with single digit nanomolar potency. Analogues 10aq and 10dq demonstrated in vivo efficacy in a murine gut retention assay. 相似文献
7.
Kitas EA Galley G Jakob-Roetne R Flohr A Wostl W Mauser H Alker AM Czech C Ozmen L David-Pierson P Reinhardt D Jacobsen H 《Bioorganic & medicinal chemistry letters》2008,18(1):304-308
A hydroxamic acid screening hit 1 was elaborated to 5,5-dimethyl-2-oxoazepane derivatives exhibiting low nanomolar inhibition of gamma-secretase, a key proteolytic enzyme involved in Alzheimer's disease. Early ADME data showed a high metabolic clearance for the geminal dimethyl analogs which could be overcome by replacement with the bioisosteric geminal difluoro group. Synthesis and structure-activity relationship are discussed and in vivo active compounds are presented. 相似文献
8.
Tomoharu Tsukada Osamu Kanno Takahiro Yamane Jun Tanaka Taishi Yoshida Akira Okuno Takeshi Shiiki Mizuki Takahashi Takahide Nishi 《Bioorganic & medicinal chemistry》2010,18(14):5346-5351
With the aim of exploring the effect of tricyclic-based FBPase inhibitors in cells and in vivo, a series of prodrugs of tricyclic phosphonates was designed and synthesized. Introducing prodrug moieties into tricyclic-based phosphonates led to the discovery of prodrug 15c, which strongly inhibited glucose production in monkey hepatocytes. Furthermore, prodrug 15c lowered blood glucose levels in fasted cynomolgus monkeys. 相似文献
9.
Sung Yun Cho Sun-Young Han Jae Du Ha Jae Wook Ryu Chong Ock Lee Heejung Jung Nam Sook Kang Hyoung Rae Kim Jong Sung Koh Jongkook Lee 《Bioorganic & medicinal chemistry letters》2010,20(14):4223-4227
We report the synthesis and biological evaluation of aminopyridines substituted with benzoxazole. The SAR of the aminopyridines was explored to improve the inhibitory activity against c-Met and to decrease hERG affinity. These studies led to the discovery of amide 24 which showed good c-Met inhibitory potency, low affinity to hERG and favorable pharmacokinetic properties in rats. 相似文献
10.
Rainer Gewald Christian Grunwald Ute Egerland 《Bioorganic & medicinal chemistry letters》2013,23(15):4308-4314
Expanding on HTS hit 4 afforded a series of [1,3,5]triazine derivatives as novel PDE4 inhibitors. The SAR development and optimization process with the emphasis on ligand efficiency and physicochemical properties led to the discovery of compound 44 as a potent, selective and orally active PDE4 inhibitor. 相似文献
11.
Li H Asberom T Bara TA Clader JW Greenlee WJ Josien HB McBriar MD Nomeir A Pissarnitski DA Rajagopalan M Xu R Zhao Z Song L Zhang L 《Bioorganic & medicinal chemistry letters》2007,17(22):6290-6294
Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. 相似文献
12.
Yeh VS Kurukulasuriya R Fung S Monzon K Chiou W Wang J Stolarik D Imade H Shapiro R Knourek-Segel V Bush E Wilcox D Nguyen PT Brune M Jacobson P Link JT 《Bioorganic & medicinal chemistry letters》2006,16(21):5555-5560
A series of metabolically stable butyrolactam 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles. 相似文献
13.
Cai ZW Wei D Schroeder GM Cornelius LA Kim K Chen XT Schmidt RJ Williams DK Tokarski JS An Y Sack JS Manne V Kamath A Zhang Y Marathe P Hunt JT Lombardo LJ Fargnoli J Borzilleri RM 《Bioorganic & medicinal chemistry letters》2008,18(11):3224-3229
A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2014,24(15):3609-3613
A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats. 相似文献
15.
Paliwal S Reichard GA Shah S Wrobleski ML Wang C Stengone C Tsui HC Xiao D Duffy RA Lachowicz JE Nomeir AA Varty GB Shih NY 《Bioorganic & medicinal chemistry letters》2008,18(14):4168-4171
Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious γ-lactam series of selective NK1 antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity. 相似文献
16.
Pinard E Alberati D Bender M Borroni E Brom V Burner S Fischer H Hainzl D Halm R Hauser N Jolidon S Lengyel J Marty HP Meyer T Moreau JL Mory R Narquizian R Norcross RD Schmid P Wermuth R Zimmerli D 《Bioorganic & medicinal chemistry letters》2010,20(23):6960-6965
Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles. 相似文献
17.
André Giroux Louise Boulet Christine Brideau Anh Chau David Claveau Bernard Côté Diane Ethier Richard Frenette Marc Gagnon Jocelyne Guay Sébastien Guiral Joseph Mancini Evelyn Martins Frédéric Massé Nathalie Méthot Denis Riendeau Joel Rubin Daigen Xu Hongping Yu Yves Ducharme Richard W. Friesen 《Bioorganic & medicinal chemistry letters》2009,19(20):5837-5841
Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 μM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development. 相似文献
18.
Mano T Stevens RW Ando K Nakao K Okumura Y Sakakibara M Okumura T Tamura T Miyamoto K 《Bioorganic & medicinal chemistry》2003,11(18):3879-3887
Replacement of the dihydroquinolinone pharmacophore of Zeneca's ZD2138 by ionizable imidazolylphenyl moiety has lead to the discovery of a novel series of potent and orally active 5-lipoxygenase (5-LO) inhibitors. The synthesis and structure-activity relationship (SAR) of this series of compounds are described herein. 相似文献
19.
Yang SW Smotryski J McElroy WT Tan Z Ho G Tulshian D Greenlee WJ Guzzi M Zhang X Mullins D Xiao L Hruza A Chan TM Rindgen D Bleickardt C Hodgson R 《Bioorganic & medicinal chemistry letters》2012,22(1):235-239
A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high affinity. From the SAR study and our lead optimization efforts, compounds 16 and 27 were found to possess potent oral antipsychotic activity in the MK-801 induced hyperactive rat model. 相似文献
20.
Kai Wang Wenwei Xu Wei Zhang Mingguang Mo Yiping Wang Jianhua Shen 《Bioorganic & medicinal chemistry letters》2013,23(10):2897-2901
This Letter reports our efforts towards the optimization of our previously identified series of imidazole and triazole derivatives that lead to the discovery of a series of orally active Lp-PLA2 inhibitors in C57 mice. These inhibitors are characterized by the presence of a diamine side chain in the molecules, such as 2c, 2f, and 4a. The introduction of the terminal-end amine succeeded in maintaining the in vitro activities at sub-nanomolar levels. The vivo activities could be greatly affected by variations in the two amines via modulating the metabolic stability and lipophilicity of the compounds. 相似文献