23877-68-1Relevant articles and documents
6,7-DIHYDRO-5H-PYRIDO[2,3-C]PYRIDAZINE DERIVATIVES AND RELATED COMPOUNDS AS BCL-XL PROTEIN INHIBITORS AND PRO-APOPTOTIC AGENTS FOR TREATING CANCER
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, (2021/02/05)
The present invention discloses 6,7-dihydro-5H-pyrido[2,3- c]pyridazine, 1,2,3,4-tetrahydroquinoline, 1H-indole, 3,4- dihydro-2H-1,4-benzoxazine, 1H-pyrrolo[2,3-b]pyridin-1-yl, 7H- pyrrolo[2,3-c]pyridazine, 5H,6H,7H,8H,9H-pyridazino[3,4-b]azepine derivatives and related compounds of formula (I) as Bcl-xL protein inhibitors for use as pro-apoptotic agents for treating cancer, autoimmune diseases or immune system diseases. Formula (I). The description discloses the preparation of exemplary compounds (e.g. pages 113 to 354 examples 1 to 221) as well as pharmacological studies with relevant data (e.g. pages 355 to 367; examples A to E; tables 1 to 5). Exemplary compounds are e.g. 2-{6-[(1,3-benzothiazol-2-yl) amino]-1,2,3,4-tetrahydroquinolin-1-yl}-1,3-thiazole-4-carboxylic acid (example 1) or e.g. 3-{1-[(adamantan-1-yl)methyl]-5- methyl-1H-pyrazol-4-yl}-6-{3-[(1,3-benzothiazol-2-yl)amino]-4- methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl]pyridine-2-carboxylic acid (example 24).
Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ERα/VEGFR-2 ligands for treatment of breast cancer
Luo, Guoshun,Li, Xinyu,Zhang, Guoqing,Wu, Chengzhe,Tang, Zhengpu,Liu, Linyi,You, Qidong,Xiang, Hua
, p. 252 - 273 (2017/09/25)
There is considerable interest in developing new SERMs as multifunctional agents in women's health. Development of dual selective estrogen receptor modulators/VEGFR-2 inhibitors (SERMs/V-2I) has been an attractive strategy for the discovery of new breast cancer therapeutic agents. Our previous efforts led to the preparation of a series of 3-aryl-4-anilino-2H-chromen-2-ones endowed with potent estrogen receptor binding affinity and anti-proliferative efficacy. In this study, various structurally related 3-aryl-4-anilino/aryloxy-2H-chromen-2-one analogues were rationally designed, synthesized and evaluated as a new chemo-type of dual ERα and VEGFR-2 inhibitors. Most of the derivatives exhibited potent activities in both enzymatic and cellular assays. SAR investigation revealed that introducing of bioisosteric O atom at the C-4 position of coumarin scaffold is beneficial to improve the inhibitory potency, especially in ERα binding affinity assay. Furthermore, most of the piperidyl substituted compounds showed better inhibitory activity against MCF-7 and Ishikawa cells than lead compounds BL-18d, tamoxifen and Vandetanib. Optimization of the hit compound, identified in an ERα binding affinity assay, led to compound 42d, exhibiting an IC50 for ERα binding affinity of 2.19 μM while retaining an excellent inhibition on VGFR-2 as well as a potent suppression on the growth of angiogenesis-related cells. In RT-PCR assay, 42d exerted significantly antiestrogenic property via suppressing the expression of progesterone receptor (PgR) mRNA in MCF-7 cells, which was consistent with the ERα antagonistic property of a selective estrogen receptor modulator. Further mechanism investigation demonstrated that compound 42d could inhibit the activation of VEGFR-2 and subsequent signaling transduction of Raf-1/MAPK/ERK pathway in MCF-7 cells. All these results together with molecular modeling studies open a new avenue for the development of multifunctional agents targeting ERα and VEGFR-2 in the therapy of some breast cancers.
Identification of a potent, selective, and orally active leukotriene A 4 hydrolase inhibitor with anti-inflammatory activity
Grice, Cheryl A.,Tays, Kevin L.,Savall, Brad M.,Wei, Jianmei,Butler, Christopher R.,Axe, Frank U.,Bembenek, Scott D.,Fourie, Anne M.,Dunford, Paul J.,Lundeen, Katherine,Coles, Fawn,Xue, Xiaohua,Riley, Jason P.,Williams, Kacy N.,Karlsson, Lars,Edwards, James P.
scheme or table, p. 4150 - 4169 (2009/07/19)
LTA4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA4H stereospecifically catalyzes the transformation of the unstable epoxide LTA4 to the diol LTB4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
