共查询到20条相似文献,搜索用时 15 毫秒
1.
Discovery of potent,selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors
Meizhong Jin Jing Wang Andrew Kleinberg Mridula Kadalbajoo Kam W. Siu Andrew Cooke Mark A. Bittner Yan Yao April Thelemann Qunsheng Ji Shripad Bhagwat Kristen M. Mulvihill Josef A. Rechka Jonathan A. Pachter Andrew P. Crew David Epstein Mark J. Mulvihill 《Bioorganic & medicinal chemistry letters》2013,23(4):979-984
This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure–activity relationships and optimization of drug metabolism and pharmacokinetic properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors. 相似文献
2.
Xiao Ding Luigi Piero Stasi Ming-Hsun Ho Baowei Zhao Hailong Wang Kai Long Qiongfeng Xu Yingxia Sang Changhui Sun Huan Hu Haihua Yu Zehong Wan Lizhen Wang Colin Edge Qian Liu Yi Li Kelly Dong Xiaoming Guan Feng Ren 《Bioorganic & medicinal chemistry letters》2018,28(9):1615-1620
Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson’s disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100?mg/kg) and mice (45?mg/kg) following oral administration. 相似文献
3.
Pál Gyulavári Bálint Szokol István Szabadkai Diána Brauswetter Péter Bánhegyi Attila Varga Péter Markó Sándor Boros Eszter Illyés Csaba Szántai-Kis Marcell Krekó Zsófia Czudor László Őrfi 《Bioorganic & medicinal chemistry letters》2018,28(19):3265-3270
Aurora kinases as regulators of cell division have become promising therapeutic targets recently. Here we report novel, low molecular weight benzothiophene-3-carboxamide derivatives designed and optimized for inhibiting Aurora kinases. The most effective compound 36 inhibits Aurora kinases in vitro in the nanomolar range and diminishes HCT 116 cell viability blocking cytokinesis and inducing apoptosis. According to western blot analysis, the lead molecule inhibits Aurora kinases equipotently to VX-680 (Tozasertib) and similarly synergizes with other targeted drugs. 相似文献
4.
Xiao Ding Xuedong Dai Kai Long Cheng Peng Daniele Andreotti Paul Bamborough Andrew J. Eatherton Colin Edge Karamjit S. Jandu Paula L. Nichols Oliver J. Philps Luigi Piero Stasi Zehong Wan Jia-Ning Xiang Kelly Dong Pamela Dossang Ming-Hsun Ho Yi Li Feng Ren 《Bioorganic & medicinal chemistry letters》2017,27(17):4034-4038
Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson’s disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability. 相似文献
5.
Liddle J Atkinson FL Barker MD Carter PS Curtis NR Davis RP Douault C Dickson MC Elwes D Garton NS Gray M Hayhow TG Hobbs CI Jones E Leach S Leavens K Lewis HD McCleary S Neu M Patel VK Preston AG Ramirez-Molina C Shipley TJ Skone PA Smithers N Somers DO Walker AL Watson RJ Weingarten GG 《Bioorganic & medicinal chemistry letters》2011,21(20):6188-6194
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model. 相似文献
6.
David B. Belanger Michael J. Williams Patrick J. Curran Amit K. Mandal Zhaoyang Meng Matthew P. Rainka Tao Yu Neng-Yang Shih M. Arshad Siddiqui Ming Liu Seema Tevar Suining Lee Lianzhu Liang Kimberly Gray Bohdan Yaremko Jennifer Jones Elizabeth B. Smith Dan B. Prelusky Andrea D. Basso 《Bioorganic & medicinal chemistry letters》2010,20(22):6739-6743
We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model. 相似文献
7.
8.
Marzena Mazur Agnieszka Bartoszewicz Barbara Dymek Magdalena Salamon Gleb Andryianau Michał Kowalski Sylwia Olejniczak Krzysztof Matyszewski Elżbieta Pluta Bartłomiej Borek Filip Stefaniak Agnieszka Zagozdzon Marcin Mazurkiewicz Robert Koralewski Wojciech Czestkowski Michał Piotrowicz Piotr Niedziejko Mariusz M. Gruza Jacek Olczak 《Bioorganic & medicinal chemistry letters》2018,28(3):310-314
This article describes our work towards the identification of a potent and selective inhibitor of mouse chitotriosidase (mCHIT1). A series of small molecule inhibitors of mCHIT1 and mAMCase have been developed from early lead compound 1. Examination of synthetized analogues led to discovery of several novel highly potent compounds. Among them compound 9 (OAT-2068) displays a remarkable 143-fold mCHIT1 vs. mAMCase selectivity. To explain the observed SAR molecular docking experiments were performed, which were in line with the experimental data from the enzymatic assays. Inhibitor 9 (OAT-2068) was found to have an excellent pharmacokinetic profile. This, together with high activity and selectivity, makes the compound an ideal and unique tool for studying the role of CHIT1 in biological models. 相似文献
9.
Yuhua He Wei Fu Liyang Du Huiqiao Yao Zhengkang Hua Jinyu Li Zhonghui Lin 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):109
Invasive fungal infections including Candidiasis and Aspergillosis are associated with considerable morbidity and mortality in immunocompromised individuals, such as cancer patients. Aurora B is a key mitotic kinase required for the cell division of eukaryotes from fungus to man. Here, we identified a novel Aurora B inhibitor GSK650394 that can inhibit the recombinant Aurora B from human and Aspergillus fumigatus, with IC50 values of 5.68 and 1.29 µM, respectively. In HeLa and HepG2 cells, GSK650394 diminishes the endogenous Aurora B activity and causes cell cycle arrest in G2/M phase. Further cell-based assays demonstrate that GSK650394 efficiently suppresses the proliferation of both cancer cells and Aspergillus fumigatus. Finally, the molecular docking calculation and site-directed mutagenesis analyses reveal the molecular mechanism of Aurora B inhibition by GSK650394. Our work is expected to provide new insight into the combinational therapy of cancer and Aspergillus fumigatus infection. 相似文献
10.
Yueliang Wang Li Xing Yinchun Ji Jiqing Ye Yang Dai Wangting Gu Jing Ai Zilan Song 《Bioorganic & medicinal chemistry letters》2019,29(6):836-838
Starting from the recently launched FLT3/AXL multi-targeted inhibitor Gilteritinib (5), we conducted a side-chain ring closure medicinal chemistry approach leading to the identification of compound 15c as a highly potent AXL inhibitor in the biochemical and cellular anti-proliferative assays, with IC50 values of 1.2 and 0.3?nM, respectively. Compared with the reference compound 5, our new discovered AXL inhibitor 15c is more potent in both assays. 相似文献
11.
Hanbiao Yang Xiao-Fa Lin Fernando Padilla Stephen D. Gabriel Gabrielle Heilek Changhua Ji Surya Sankuratri André deRosier Pamela Berry David M. Rotstein 《Bioorganic & medicinal chemistry letters》2009,19(1):209-213
Replacement of the cyclic carbamate in our previously disclosed 1-oxa-3,9-diazaspiro[5.5]undecan-2-one template led to the discovery of two novel series of 3,9-diazaspiro[5.5]undecane and undeca-2-one CCR5 antagonists. The synthesis, SAR, and antiviral activities of these two series are described. One compound (32) was found to have attractive combination of antiviral potency, selectivity, and pharmacokinetic profile. The asymmetric synthesis of 32 was also accomplished and both enantiomers were equally potent. 相似文献
12.
Saravanan Parthasarathy Kenneth Henry Huaxing Pei Josh Clayton Mark Rempala Deidre Johns Oscar De Frutos Pablo Garcia Carlos Mateos Sehila Pleite Yong Wang Stephanie Stout Bradley Condon Sheela Ashok Zhohai Lu William Ehlhardt Tom Raub Mei Lai Timothy P. Burkholder 《Bioorganic & medicinal chemistry letters》2018,28(10):1887-1891
During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model. 相似文献
13.
Sobhana Babu Boga Abdul-Basit Alhassan Jian Liu Deodial Guiadeen Arto Krikorian Xiaolei Gao James Wang Younong Yu Rajan Anand Shilan Liu Chundao Yang Hao Wu Jiaqiang Cai Hugh Zhu Jagdish Desai Kevin Maloney Ying-Duo Gao Thierry O. Fischmann Joseph A. Kozlowski 《Bioorganic & medicinal chemistry letters》2017,27(16):3939-3943
8-Amino-imidazo[1,5-a]pyrazine-based Bruton’s tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles. 相似文献
14.
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
15.
Richard Ducray Clifford D. JonesFrederic H. Jung Iain SimpsonJon Curwen Martin Pass 《Bioorganic & medicinal chemistry letters》2011,21(16):4702-4704
Following the discovery of imidazopyridine 1 as a potent IGF-1R tyrosine kinase inhibitor, the aniline part has been modified with the aim to optimize the properties of this series. The structure-activity relationships against IGF-1R kinase activity as well as inhibition of the hERG ion channel are discussed. 相似文献
16.
Takeshi Fukuda Riki Goto Toshihiro Kiho Kenjiro Ueda Sumie Muramatsu Masami Hashimoto Anri Aki Kengo Watanabe Naoki Tanaka 《Bioorganic & medicinal chemistry letters》2017,27(16):3716-3722
Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(16):3748-3752
A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed. 相似文献
18.
Fleur M. Ferguson Zainab M. Doctor Apirat Chaikuad Taebo Sim Nam Doo Kim Stefan Knapp Nathanael S. Gray 《Bioorganic & medicinal chemistry letters》2017,27(18):4405-4408
Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity. 相似文献
19.
Discovery of an Aurora kinase inhibitor through site-specific dynamic combinatorial chemistry 总被引:1,自引:0,他引:1
Cancilla MT He MM Viswanathan N Simmons RL Taylor M Fung AD Cao K Erlanson DA 《Bioorganic & medicinal chemistry letters》2008,18(14):3978-3981
We demonstrate a fragment-based lead discovery method that combines site-directed ligand discovery with dynamic combinatorial chemistry. Our technique targets dynamic combinatorial screening to a specified region of a protein by using reversible disulfide chemistry. We have used this technology to rapidly identify inhibitors of the drug target Aurora A that span the purine-binding site and the adaptive pocket of the kinase. The binding mode of a noncovalent inhibitor has been further characterized through crystallography. 相似文献
20.
Oslob JD Romanowski MJ Allen DA Baskaran S Bui M Elling RA Flanagan WM Fung AD Hanan EJ Harris S Heumann SA Hoch U Jacobs JW Lam J Lawrence CE McDowell RS Nannini MA Shen W Silverman JA Sopko MM Tangonan BT Teague J Yoburn JC Yu CH Zhong M Zimmerman KM O'Brien T Lew W 《Bioorganic & medicinal chemistry letters》2008,18(17):4880-4884
This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models. 相似文献