Ring-fused pyrazole derivatives as potent inhibitors of lymphocyte-specific kinase (Lck): Structure, synthesis, and SAR

Takayama, Tetsuo; Umemiya, Hiroki; Amada, Hideaki; Yabuuchi, Tetsuya; Koami, Takeshi; Shiozawa, Fumiyasu; Oka, Yusuke; Takaoka, Akiko; Yamaguchi, Akie; Endo, Mayumi; Sato, Masakazu

doi:10.1016/j.bmcl.2009.11.013

Cited by 15 publications

(6 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Dimroth isomer trifluoro-N-imidazo[1,2a]pyridine-3-ylacetamide was also detected by HPLC, T r = 1.25 min (22%). Analysis of 11: 1 H NMR (CDCl 3 , 300 MHz) δ 5.56 (br s, 1H), 6.90 (dd, 1H, J = 6.9, 7.8 Hz), 7.28 (dd, 1H, J = 9.1, 7.8 Hz), 7.49 (d, 1H, J = 9.1 Hz), 8.16 (d, 1H, J = 6.8 Hz), 8.18 (s, 1H); 13 C NMR (CDCl 3 , 75 MHz) δ 102.9, 113.3, 114.5 (q), 116.4, 126.0, 126.2, 139.3, 142.0, 154.9 (q); 19 Synthesis of 12a−e. To a suspension of 1 g of compound 11 (4.36 mmol) in 9 mL of aqueous 5 N sodium hydroxide solution was added 1 mL of THF.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Among the different classes of diazepines, the [1,3]diazepines have been studied to a minor extent although their derivatives are also of interest due to their ability to bind multiple therapeutic targets. As an example, [1,3]diazepines have shown inhibitory effects on HIV-1 protease, 18 lymphocyte-specific kinase (Lck), 19 AMP deaminase, 20 adenosine deaminase, and guanase, 21 as well as cytotoxic effects on Jurkat and glial cells 22 (for examples of biologically active [1,3]diazepines, see Figure 1). Consequently, the development of efficient methodologies for the synthesis of new heterocyclefused [1,3]diazepine scaffolds could be of value for subsequent biological screening programs.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Selective C-Acylation of 2-Aminoimidazo[1,2-a]pyridine: Application to the Synthesis of Imidazopyridine-Fused [1,3]Diazepinones

et al. 2012

View full text Add to dashboard Cite

show abstract

Section: ■ Experimental Sectionmentioning

confidence: 99%

mentioning

confidence: 99%

Selective C-Acylation of 2-Aminoimidazo[1,2-a]pyridine: Application to the Synthesis of Imidazopyridine-Fused [1,3]Diazepinones

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Patients with LCK de ciency frequently present with immune dysregulation and autoimmunity. Over expression of LCK leads to large number of other diseases like cancer, asthma, diabetes 1, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, in ammatory bowel diseases (crohn's disease and ulcerative colitis), organ graft rejection, atherosclerosis, hypersensitivity reactions, polyarthritis, dermatomyositis [43,44]. Since LCK is involved in T cell proliferation and differentiation, therefore, new small molecules with LCK inhibitory activity can be of great relevance to treat T cell mediated diseases.…”

Section: Discussionmentioning

confidence: 99%

Molecular Profiling of Core Immune-Escape Genes Highlights LCK Has Potential to Reshape TME in Melanoma

Zhang

Xiang

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: The game between the immune system of the organism and the tumor is a dynamic course of events. Once the escape phase is reached, the tumor will overcome the limitations of the immune system and the tumor will progress. Objective: This study aimed to determine the potential tumor environment-based prognostic biomarkers related to immunotherapy in melanoma. Methods: 471 tumor samples and 398 normal samples were extracted from The Cancer Genome Atlas and The Genotype-Tissue Expression. Furthermore, a core set of immune-escape genes were collected from previous studies and a set of immune-related genes were obtained from IMMPORT database. Through overlapping these two sets of genes, a set of core immune-escape related genes were identified. In the next place, we conducted a systematic analysis of core immune-escape related genes through The Cancer Genome Atlas cohort and identified independent prognostic factors in melanoma. Through CIBERSORT, ssGSEA algorithm and TIMER database, we explored the potential of independent prognostic factors to reshape the tumor microenvironment.Results: Through Kaplan-Meier as well as univariate cox regression analysis of expression profiles and clinical information obtained from the TCGA cohort, we found that high LCK expression was associated with prolonged overall survival. In addition, the expression level of LCK was significantly correlated with the dysregulation of the infiltration level of immune cells in the tumor microenvironment. Conclusions: In this study, we determined LCK as a biomarker that is significantly associated with tumor environment and has significant prognostic significance. Meanwhile, immunotherapeutic approaches targeting LCK in tumor cells may provide a new perspective for the treatment of melanoma.

show abstract

“…Several groups have been interested in the synthesis and characterization of Lck inhibitors 150–152 . However, only Taishgo laboratories have described kinase inhibitors with a pyrazole structure fused to a 1,3‐diazepine scaffold 153 …”

Section: 3‐diazepine Derivatives As Enzyme Inhibitorsmentioning

confidence: 99%

“…In 2010, Takaya et al 153 described the synthesis of about 30 compounds with the pyrazole‐fused 1,3‐diazepine structure, as well as their inhibitory activity on the enzyme and on the cell immune response (mixed lymphocyte reaction). All showed inhibitory activity against Lck in the nanomolar range with more or less activity on cell lines.…”

Section: 3‐diazepine Derivatives As Enzyme Inhibitorsmentioning

confidence: 99%

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Malki

Martinez

Masurier

2021

Medicinal Research Reviews

View full text Add to dashboard Cite

Privileged structures have been widely used as effective templates for drug discovery. While benzo‐1,4‐diazepine constitutes the first historical example of such a structure, the 1,3 analogue is just as rich in terms of applications in medicinal chemistry. The 1,3‐diazepine moiety is present in numerous biological active compounds including natural products, and is used to design compounds displaying a large range of biological activities. It is present in the clinically used anticancer compound pentostatin, in several recent FDA approved β‐lactamase inhibitors (e.g., avibactam) and also in coformycin, a natural product known as a ring‐expanded purine analogue displaying antiviral and anticancer activities. Several other 1,3‐diazepine containing compounds have entered into clinical trials. This heterocyclic structure has been and is still widely used in medicinal chemistry to design enzyme inhibitors, GPCR ligands, and so forth. This review endeavours to highlight the main use of the 1,3‐diazepine scaffold and its derivatives, and their applications in medicinal chemistry, drug design, and therapy. We will focus more particularly on the development of enzyme inhibitors incorporating this scaffold, with a strong emphasis on the molecular interactions involved in the inhibition mechanism.

show abstract

Ring-fused pyrazole derivatives as potent inhibitors of lymphocyte-specific kinase (Lck): Structure, synthesis, and SAR

Cited by 15 publications

References 13 publications

Selective C-Acylation of 2-Aminoimidazo[1,2-a]pyridine: Application to the Synthesis of Imidazopyridine-Fused [1,3]Diazepinones

Selective C-Acylation of 2-Aminoimidazo[1,2-a]pyridine: Application to the Synthesis of Imidazopyridine-Fused [1,3]Diazepinones

Molecular Profiling of Core Immune-Escape Genes Highlights LCK Has Potential to Reshape TME in Melanoma

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Contact Info

Product

Resources

About