共查询到20条相似文献,搜索用时 15 毫秒
1.
Maria Gabriella Brasca Clara Albanese Rachele Alzani Raffaella Amici Nilla Avanzi Dario Ballinari James Bischoff Daniela Borghi Elena Casale Valter Croci Francesco Fiorentini Antonella Isacchi Ciro Mercurio Marcella Nesi Paolo Orsini Wilma Pastori Enrico Pesenti Paolo Pevarello Patrick Roussel Mario Varasi Marina Ciomei 《Bioorganic & medicinal chemistry》2010,18(5):1844-1853
We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors. 相似文献
2.
Alla Korepanova Kenton L. Longenecker Steve D. Pratt Sanjay C. Panchal Richard F. Clark Marc Lake Sujatha M. Gopalakrishnan Diana Raich Chaohong Sun Andrew M. Petros 《Bioorganic & medicinal chemistry letters》2018,28(3):437-440
NAMPT expression is elevated in many cancers, making this protein a potential target for anticancer therapy. We have carried out both NMR based and TR-FRET based fragment screens against human NAMPT and identified six novel binders with a range of potencies. Co-crystal structures were obtained for two of the fragments bound to NAMPT while for the other four fragments force-field driven docking was employed to generate a bound pose. Based on structural insights arising from comparison of the bound fragment poses to that of bound FK866 we were able to synthetically elaborate one of the fragments into a potent NAMPT inhibitor. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(11):2571-2577
We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands. 相似文献
4.
Kurt G. Pike Karine Malagu Marc G. Hummersone Keith A. Menear Heather M.E. Duggan Sylvie Gomez Niall M.B. Martin Linette Ruston Sarah L. Pass Martin Pass 《Bioorganic & medicinal chemistry letters》2013,23(5):1212-1216
The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC50, led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21). 相似文献
5.
Hirayama F Koshio H Katayama N Kurihara H Taniuchi Y Sato K Hisamichi N Sakai-Moritani Y Kawasaki T Matsumoto Y Yanagisawa I 《Bioorganic & medicinal chemistry》2002,10(5):1509-1523
Since Factor Xa (FXa) is well known to play a central role in thrombosis and hemostasis, inhibition of FXa is an attractive target for antithrombotic strategies. As a part of our investigation of a non-peptide, orally available FXa inhibitor, we found that a series of N-[(7-amidino-2-naphthyl)methyl]aniline derivatives possessed potent and selective inhibitory activities. Structure--activity relationship (SAR) of the substituent (R(1)) on the central aniline moiety suggested that increasing lipophilicity caused a detrimental effect on anticoagulant activity (prothrombin time assay) in plasma. Several compounds bearing a hydrophilic substituent in R(1) showed not only potent FXa inhibitory activities but also high anticoagulant activities. The best compound in this series was sulfamoylacetic acid derivative (YM-60828) which was a potent, selective and orally bioavailable FXa inhibitor and was chosen for clinical development. 相似文献
6.
Characterization of novel imidazole derivative, JM-8686, a potent inhibitor of allene oxide synthase
The inhibitory properties of a first synthetic jasmonic acid biosynthesis inhibitor, JM-8686, were investigated. Steady-state kinetic analysis indicates that the compound is a competitive inhibitor of allene oxide synthase (AOS) with a K(i) value of approximate 0.62+/-0.15 microM. Dialysis experiment indicates that AOS inactivation by JM-8686 is reversible. The optical difference spectroscopy analysis of JM-8686 and AOS interaction indicates that JM-8686 induced type II binding spectra with a K(d) value of approximate 1.6+/-0.2 microM, suggesting that JM-8686 binds to the prosthetic heme iron of AOS. Comparison of the inhibitory potency of the compound against HPL (CYP74B) from tomato revealed that JM-8686 was a highly selective inhibitor for AOS. 相似文献
7.
Mete A Bowers K Chevalier E Donald DK Edwards H Escott KJ Ford R Grime K Millichip I Teobald B Russell V 《Bioorganic & medicinal chemistry letters》2011,21(24):7440-7446
The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD. 相似文献
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10.
Xiong Y Wiltsie J Woods A Guo J Pivnichny JV Tang W Bansal A Cummings RT Cunningham BR Friedlander AM Douglas CM Salowe SP Zaller DM Scolnick EM Schmatz DM Bartizal K Hermes JD MacCoss M Chapman KT 《Bioorganic & medicinal chemistry letters》2006,16(4):964-968
A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies. 相似文献
11.
B. Narasimhulu Naidu Michael A. Walker Margaret E. Sorenson Yasutsugu Ueda John D. Matiskella Timothy P. Connolly Ira B. Dicker Zeyu Lin Sagarika Bollini Brian J. Terry Helen Higley Ming Zheng Dawn D. Parker Dedong Wu Stephen Adams Mark R. Krystal Nicholas A. Meanwell 《Bioorganic & medicinal chemistry letters》2018,28(12):2124-2130
BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials. 相似文献
12.
Yongtao Li Qingxiang Guo Chao Zhang Zhi Huang Tianqi Wang Xin Wang Xiang Wang Guangwei Xu Yanhua Liu Shengyong Yang Yan Fan Rong Xiang 《Bioorganic & medicinal chemistry letters》2017,27(15):3231-3237
A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC50 = 12 nM. It effectively induced apoptosis in breast and lung cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with compound 4d showed significant suppression of cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application. 相似文献
13.
David Sperandio Vangelis Aktoudianakis Kerim Babaoglu Xiaowu Chen Kristyna Elbel Gregory Chin Britton Corkey Jinfa Du Bob Jiang Tetsuya Kobayashi Richard Mackman Ruben Martinez Hai Yang Jeff Zablocki Saritha Kusam Kim Jordan Heather Webb Jamie G. Bates David G. Breckenridge 《Bioorganic & medicinal chemistry》2019,27(3):457-469
14.
Macdonald SJ Dowle MD Harrison LA Shah P Johnson MR Inglis GG Clarke GD Smith RA Humphreys D Molloy CR Amour A Dixon M Murkitt G Godward RE Padfield T Skarzynski T Singh OM Kumar KA Fleetwood G Hodgson ST Hardy GW Finch H 《Bioorganic & medicinal chemistry letters》2001,11(7):895-898
The discovery of a potent intracellular inhibitor of human neutrophil elastase which is orally active and has a long duration of action is described. The pharmacodynamic and pharmacokinetic properties of a trans-lactam development candidate, GW311616A, are described. 相似文献
15.
The discovery of RFI-641 as a potent and selective inhibitor of the respiratory syncytial virus 总被引:4,自引:0,他引:4
The design and synthesis of a new potent and selective inhibitor of the respiratory syncytial virus are described. This compound, RFI-641, emerged from analysis of the structure-activity relationship in a series of biphenyl triazine anionic compounds possessing specific anti-RSV activity. The key synthetic step involves coupling of diaminobiphenyl 11 with two equivalents of chlorotriazine 10 under microwave conditions. RFI-641 inhibited RSV in vitro and in vivo models. 相似文献
16.
David Bebbington Hayley Binch Jean-Damien Charrier Simon Everitt Damien Fraysse Julian Golec David Kay Ronald Knegtel Chau Mak Francesca Mazzei Andrew Miller Michael Mortimore Michael O’Donnell Sanjay Patel Francoise Pierard Joanne Pinder John Pollard Sharn Ramaya Daniel Robinson Alistair Rutherford James Westcott 《Bioorganic & medicinal chemistry letters》2009,19(13):3586-3592
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) containing the T315I mutation. 相似文献
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18.
Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping 总被引:1,自引:0,他引:1
Richardson CM Nunns CL Williamson DS Parratt MJ Dokurno P Howes R Borgognoni J Drysdale MJ Finch H Hubbard RE Jackson PS Kierstan P Lentzen G Moore JD Murray JB Simmonite H Surgenor AE Torrance CJ 《Bioorganic & medicinal chemistry letters》2007,17(14):3880-3885
Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode. 相似文献
19.
Erlanson DA Arndt JW Cancilla MT Cao K Elling RA English N Friedman J Hansen SK Hession C Joseph I Kumaravel G Lee WC Lind KE McDowell RS Miatkowski K Nguyen C Nguyen TB Park S Pathan N Penny DM Romanowski MJ Scott D Silvian L Simmons RL Tangonan BT Yang W Sun L 《Bioorganic & medicinal chemistry letters》2011,21(10):3078-3083
We report the use of a fragment-based lead discovery method, Tethering with extenders, to discover a pyridinone fragment that binds in an adaptive site of the protein PDK1. With subsequent medicinal chemistry, this led to the discovery of a potent and highly selective inhibitor of PDK1, which binds in the ‘DFG-out’ conformation. 相似文献
20.
Smith ND Reger TS Payne J Zunic J Lorrain D Correa L Stock N Cramer M Chen W Yang J Prasit P Munoz B 《Bioorganic & medicinal chemistry letters》2005,15(13):3197-3200
A water soluble choline prodrug (17) of a COX-2 selective inhibitor (16) suitable for intravenous dosing in models of cerebral ischemia has been developed. Constant infusion studies using 17 demonstrate that extrapolated brain levels of 16 may be maintained for over 24h in rats. 相似文献