共查询到20条相似文献,搜索用时 15 毫秒
1.
Hit-to-lead studies: the discovery of potent,orally bioavailable triazolethiol CXCR2 receptor antagonists 总被引:2,自引:0,他引:2
Baxter A Bennion C Bent J Boden K Brough S Cooper A Kinchin E Kindon N McInally T Mortimore M Roberts B Unitt J 《Bioorganic & medicinal chemistry letters》2003,13(16):2625-2628
A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45. 相似文献
2.
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
3.
Baxter A Cooper A Kinchin E Moakes K Unitt J Wallace A 《Bioorganic & medicinal chemistry letters》2006,16(4):960-963
A Hit-to-Lead optimisation programme was carried out on a high throughput screening hit, the thiazolopyrimidine 1, resulting in the discovery of the potent, orally bioavailable CXCR2 antagonist 29. 相似文献
4.
Snow RJ Abeywardane A Campbell S Lord J Kashem MA Khine HH King J Kowalski JA Pullen SS Roma T Roth GP Sarko CR Wilson NS Winters MP Wolak JP Cywin CL 《Bioorganic & medicinal chemistry letters》2007,17(13):3660-3665
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed. 相似文献
5.
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
6.
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
7.
Ho GD Yang SW Smotryski J Bercovici A Nechuta T Smith EM McElroy W Tan Z Tulshian D McKittrick B Greenlee WJ Hruza A Xiao L Rindgen D Mullins D Guzzi M Zhang X Bleickardt C Hodgson R 《Bioorganic & medicinal chemistry letters》2012,22(2):1019-1022
High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a ~6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats. 相似文献
8.
Atkinson KA Beretta EE Brown JA Castrodad M Chen Y Cosgrove JM Du P Litchfield J Makowski M Martin K McLellan TJ Neagu C Perry DA Piotrowski DW Steppan CM Trilles R 《Bioorganic & medicinal chemistry letters》2011,21(6):1621-1625
A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse. 相似文献
9.
Guthikonda RN Shah SK Pacholok SG Humes JL Mumford RA Grant SK Chabin RM Green BG Tsou N Ball R Fletcher DS Luell S Euan MacIntyre D Maccoss M 《Bioorganic & medicinal chemistry letters》2005,15(8):1997-2001
Syntheses and nitric oxide synthase inhibitory activity of cyclic amidines containing 5,6- 6,6- and 7,6-fused systems are described. X-ray structure determination facilitated the assignment of the stereochemistry of the most active compounds perhydro-2-iminoisoquinoline (8a) and perhydro-2-iminopyrindine (10a). Both 8a and 10a are very potent inhibitors of iNOS, with excellent selectivity over eNOS and they are orally active in rats with long duration suitable for once or twice a day dosing. 相似文献
10.
Birch AM Kenny PW Oikonomakos NG Otterbein L Schofield P Whittamore PR Whalley DP 《Bioorganic & medicinal chemistry letters》2007,17(2):394-399
A series of substituted 3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site. 相似文献
11.
Jitendra A. Sattigeri Malvika Garg Pragya Bhateja Ajay Soni Abdul Rehman Abdul Rauf Mahendrakumar Gupta Mahesh S. Deshmukh Tarun Jain Nidhi Alekar Tarani Kanta Barman Paras Jha Tridib Chaira Ramesh B. Bambal Dilip J. Upadhyay Takahide Nishi 《Bioorganic & medicinal chemistry letters》2018,28(17):2993-2997
FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice. 相似文献
12.
Y Leblanc P Roy S Boyce C Brideau C C Chan S Charleson R Gordon E Grimm J Guay S Léger C S Li D Riendeau D Visco Z Wang J Webb L J Xu P Prasit 《Bioorganic & medicinal chemistry letters》1999,9(15):2207-2212
Extensive SAR has been established in the alkoxy lactone series and this has lead to the discovery of DFP (5,5-dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanon e), a potent COX-2 inhibitor exhibiting in vivo efficacy in all models studied. 相似文献
13.
Sakya SM DeMello KM Minich ML Rast B Shavnya A Rafka RJ Koss DA Cheng H Li J Jaynes BH Ziegler CB Mann DW Petras CF Seibel SB Silvia AM George DM Lund LA St Denis S Hickman A Haven ML Lynch MP 《Bioorganic & medicinal chemistry letters》2006,16(2):288-292
Structure-activity relationship (SAR) studies of the novel 2-[3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl]-5-methanesulfonyl (SO(2)Me)/sulfamoyl (SO(2)NH(2))-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of 2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats. 相似文献
14.
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
15.
Yoshihiro Kato Motoji Kawasaki Tomohiro Nigo Shunya Nakamura Akira Fusano Yasuhiro Teranishi Mari N. Ito Takaaki Sumiyoshi 《Bioorganic & medicinal chemistry》2013,21(18):5851-5854
A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation. 相似文献
16.
Côté B Boulet L Brideau C Claveau D Ethier D Frenette R Gagnon M Giroux A Guay J Guiral S Mancini J Martins E Massé F Méthot N Riendeau D Rubin J Xu D Yu H Ducharme Y Friesen RW 《Bioorganic & medicinal chemistry letters》2007,17(24):6816-6820
Phenanthrene imidazole 3 (MF63) has been identified as a novel potent, selective, and orally active mPGES-1 inhibitor. This new series was developed by lead optimization of a hit from an internal HTS campaign. Compound 3 is significantly more potent than the previously reported indole carboxylic acid 1 with an A549 whole cell IC50 of 0.42 μM (50% FBS) and a human whole blood IC50 of 1.3 μM. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model when orally dosed at 30 and 100 mg/kg. 相似文献
17.
Ballard P Barlaam BC Bradbury RH Dishington A Hennequin LF Hickinson DM Hollingsworth IM Kettle JG Klinowska T Ogilvie DJ Pearson SE Scott JS Suleman A Whittaker R Williams EJ Wood R Wright L 《Bioorganic & medicinal chemistry letters》2007,17(22):6326-6329
Neutral 5-substituted 4-anilinoquinazolines addressed high in vivo clearance and phospholipidosis associated with previous basic compounds. A representative compound 8a inhibited tumor growth in a mouse xenograft model when co-administered with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT), and data are consistent with pharmacology primarily reflecting inhibition of erbB2 receptor tyrosine kinase. 相似文献
18.
Barlaam B Acton DG Ballard P Bradbury RH Cross D Ducray R Germain H Hudson K Klinowska T Magnien F Ogilvie DJ Olivier A Ross HS Smith R Trigwell CB Vautier M Wright L 《Bioorganic & medicinal chemistry letters》2008,18(6):1799-1803
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration. 相似文献
19.
Matthew A.J. Duncton Eugene L. Piatnitski Chekler Reeti Katoch-Rouse Dan Sherman Wai C. Wong Leon M. Smith Joel K. Kawakami Alexander S. Kiselyov Daniel L. Milligan Chris Balagtas Yaron R. Hadari Ying Wang Sheetal N. Patel Robin L. Rolster James R. Tonra David Surguladze Stan Mitelman Paul Kussie Peter Bohlen Jacqueline F. Doody 《Bioorganic & medicinal chemistry》2009,17(2):731-740
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice. 相似文献
20.
Michael P. DeNinno Melissa Andrews Andrew S. Bell Yue Chen Cynthia Eller-Zarbo Nan Eshelby John B. Etienne Dianna E. Moore Michael J. Palmer Michael S. Visser Li J. Yu William J. Zavadoski E. Michael Gibbs 《Bioorganic & medicinal chemistry letters》2009,19(9):2537-2541
Starting from a non-selective pyrazolo-pyrimidone lead, the sequential use of parallel medicinal chemistry and directed synthesis led to the discovery of potent, highly selective, and orally bioavailable PDE9 inhibitors. The availability of these tools allowed for a thorough evaluation of the therapeutic potential of PDE9 inhibition. 相似文献