共查询到20条相似文献,搜索用时 0 毫秒
1.
Nagarajan Muthukaman Macchindra Tambe Sanjay Deshmukh Dnyandeo Pisal Shital Tondlekar Mahamadhanif Shaikh Neelam Sarode Vidya G. Kattige Monali Pisat Pooja Sawant Srinivasa Honnegowda Vikas Karande Abhay Kulkarni Dayanidhi Behera Satyawan B. Jadhav Ramchandra R. Sangana Girish S. Gudi Neelima Khairatkar-Joshi Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2017,27(23):5131-5138
This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50?nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3?mg/kg in guinea pig. 相似文献
2.
Yulong Xu Xicheng Yang Yiyi Chen Hao Chen Huijiao Sun Wei Li Qiong Xie Linqian Yu Liming Shao 《Bioorganic & medicinal chemistry letters》2018,28(12):2148-2152
A series of structurally novel proteasome inhibitors 1–12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC50?=?9.7?nM) to bortezomib (IC50?=?8.3?nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization. 相似文献
3.
Jun-Zheng Liu Shu-En Zhang Feilin Nie Ying Yang Yan-Bo Tang Wenwen Yin Jin-Ying Tian Fei Ye Zhiyan Xiao 《Bioorganic & medicinal chemistry letters》2013,23(23):6217-6222
An integrated molecular design strategy combining pharmacophore recognition and scaffold hopping was exploited to discover novel PTP1B inhibitors based on the known PTP1B inhibitor Ertiprotafib. A composite pharmacophore model was proposed from the interaction mode of Ertiprotafib, and 21 diverse molecules from five distinct structural classes were designed and synthesized accordingly. New compounds with considerable inhibition against PTP1B were identified from each series, and the most active compound 3a showed IC50 value of 1.3 μmol L?1 against human recombinant PTP1B. Docking study indicated that the new inhibitors assumed binding modes similar to that of Ertiprotafib. 相似文献
4.
Allan AC Billinton A Brown SH Chowdhury A Eatherton AJ Fieldhouse C Giblin GM Goldsmith P Hall A Hurst DN Naylor A Rawlings DA Sime M Scoccitti T Theobald PJ 《Bioorganic & medicinal chemistry letters》2011,21(14):4343-4348
We describe the discovery and optimization of a novel series of benzofuran EP1 antagonists, leading to the identification of 26d, a novel nonacidic EP1 antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(21):4969-4975
The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity. 相似文献
6.
Cyclin-dependent kinases (CDKs) are promising drug targets for various human diseases, especially for cancers. Scaffold hopping strategy was applied on CAN508, a known selective CDK9 inhibitor, and a series of pyrazolo[3,4-b]pyridine compounds were synthesized and evaluated in vitro as CDK2 and CDK9 inhibitors. Most compounds exhibited moderate to potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems. Among them, compound 2e showed IC50 values of 0.36?μM for CDK2 and 1.8?μM for CDK9, respectively. Notably, the scaffold alteration seems to cause a shift in the selectivity profile of the inhibitors. In contrast to CAN508, compound 2k demonstrated remarkable selectivity toward CDK2 (265-fold over CDK9). Docking studies on compound 2k provided hints for further design of more potent and selective CDK2/CDK9 inhibitors. 相似文献
7.
Dong Q Dougan DR Gong X Halkowycz P Jin B Kanouni T O'Connell SM Scorah N Shi L Wallace MB Zhou F 《Bioorganic & medicinal chemistry letters》2011,21(5):1315-1319
A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment. 相似文献
8.
Sonia Martínez González Ana Isabel Hernández Rosa María Álvarez Antonio Rodríguez Francisco Ramos-Lima James R. Bischoff María Isabel Albarrán Antonio Cebriá Elena Hernández-Encinas Jennifer García-Arocha David Cebrián Carmen Blanco-Aparicio Joaquín Pastor 《Bioorganic & medicinal chemistry letters》2017,27(21):4794-4799
A scaffold hopping strategy, including intellectual property availability assessment, was successfully applied for the discovery of novel PI3K inhibitors. Compounds were designed based on the chemical structure of the lead compound ETP-46321, a potent PI3K inhibitor, previously reported by our group. The new generated compounds showed good in vitro potency and selectivity, proved to inhibit potently the phosphorylation of AKTSer473 in cells and demonstrated to be orally bioavailable, thus becoming potential back-up candidates for ETP-46321. 相似文献
9.
Hongyue Li Tongliang Zhou Hui Liu Fengrong Xu Yan Niu Chao Wang Lei Liang Ping Xu 《Bioorganic & medicinal chemistry letters》2017,27(10):2221-2224
A series of Schiff base ligands (L1–L5) and their cobalt(II) complexes (1–5) were designed and synthesized for MEK1 binding experiment. The biological evaluation results showed that Bis(N,N′-disalicylidene)-3,4-phenylenediamine-cobalt(II) 1 and Bis(N,N′-disalicylidene)-1,2-cyclohexanediamine-cobalt(II) 2 are much more effective than the parent Schiff bases (L1 and L2). Importantly, 2 exhibited MEK1 binding affinity with IC5071 nM, which is so far the best result for metal complexes and more potent than U0126 (7.02 μM) and AZD6244 (2.20 μM). Docking study was used to elucidate the binding modes of complex 2 with MEK1. Thus cobalt(II) complex 2 may be further developed as a novel MEK1 inhibitor. 相似文献
10.
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
11.
12.
Kosuke Anan Moriyasu Masui Aya Tazawa Minoru Tomida Yoshihiro Haga Masaharu Kume Shoichi Yamamoto Shunji Shinohara Hiroki Tsuji Shinji Shimada Shigenori Yagi Nobuyoshi Hasebe Hiroyuki Kai 《Bioorganic & medicinal chemistry letters》2019,29(9):1143-1147
Selective N-methyl-d-aspartate receptor subunit 2B (NR2B) antagonists show potential as analgesic drugs, and do not cause side effects associated with non-selective N-methyl-d-aspartate (NMDA) antagonists. Using a scaffold-hopping approach, we previously identified isoxazole derivative 4 as a potent selective NR2B antagonist. In this study, further scaffold hopping of isoxazole derivative 4 and optimization of its pharmacokinetic profile led to the discovery of the orally bioavailable compound 6v. In a rat study of analgesia, 6v demonstrated analgesic effects against neuropathic pain. 相似文献
13.
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
14.
《Bioorganic & medicinal chemistry letters》2020,30(19):127456
The protein kinase TNK2 (ACK1) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role transmitting cell survival, growth and proliferative signals via modification of multiple downstream effectors by unique tyrosine phosphorylation events. Scaffold morphing based on our previous TNK2 inhibitor XMD8-87 identified urea 17 from which we developed the potent and selective compound 32. A co-crystal structure was obtained showing 32 interacting primarily with the main chain atoms of an alanine residue of the hinge region. Additional H-bonds exist between the urea NHs and the Thr205 and Asp270 residues. 相似文献
15.
Isshiki Y Kohchi Y Iikura H Matsubara Y Asoh K Murata T Kohchi M Mizuguchi E Tsujii S Hattori K Miura T Yoshimura Y Aida S Miwa M Saitoh R Murao N Okabe H Belunis C Janson C Lukacs C Schück V Shimma N 《Bioorganic & medicinal chemistry letters》2011,21(6):1795-1801
The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study. 相似文献
16.
Hyunjin M. Kim Michelle D. Smith Jae-Hun Kim Mary Ann Caplen Tin Yau Chan Brian A. McKittrick John A. Cook Margaret van Heek Jean Lachowicz 《Bioorganic & medicinal chemistry letters》2013,23(23):6410-6414
A scaffold hopping strategy was successfully applied in discovering 2-aminooxazole amides as potent DGAT1 inhibitors for the treatment of dyslipidemia. Further optimization in potency and PK properties resulted in a lead series with oral in vivo efficacy in a mouse postprandial triglyceridemia (PPTG) assay. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(4):1067-1070
This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclinical model of schizophrenia (prepulse inhibition). 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(4):1062-1066
This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this novel series and a number of other piperidine bioisosteric cores. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(10):2383-2387
Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantly improved in vitro activity and oral exposure, to elevate GLP1 acutely in an in vivo mouse model at a dose of 10 mg/kg. 相似文献
20.
Songwen Lin Chunyang Wang Ming Ji Deyu Wu Yuanhao Lv Li Sheng Fangbin Han Yi Dong Kehui Zhang Yakun Yang Yan Li Xiaoguang Chen Heng Xu 《Bioorganic & medicinal chemistry》2018,26(3):637-646
A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile. 相似文献