Orally bioavailable Syk inhibitors with activity in a rat PK/PD model

Thoma, Gebhard; Veenstra, Siem J.; Strang, Ross S.; Blanz, Joachim; Vangrevelinghe, Eric; Berghausen, Joerg; Lee, Christian C.; Zerwes, Hans‐Günter

doi:10.1016/j.bmcl.2015.08.037

Cited by 7 publications

(8 citation statements)

References 32 publications

(9 reference statements)

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“…Therefore, several pharmaceutical companies, as well as academic institutions, have invested in the discovery of drug candidates against SYK. Several promising compounds based on naphthyridines, pyrimidine, imidazopyrimidine, and pyrido-thiazole scaffolds were identified during early drug development attempts against SYK but were not considered for clinical use due to poor pharmacokinetic profiles ( Farmer et al., 2008 ; Hirabayashi et al., 2008 ; Liddle et al., 2011 ; Thoma et al., 2015b ). However, some potential compounds such as PRT062607, R343, R112, and entospletinib (GS-9973) are among the SYK inhibitors that have entered clinical trials and are being examined for a variety of therapeutic uses ( Liu and Mamorska-Dyga, 2017 ; Shao et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors

Kumar

Parate

Danishuddin

et al. 2022

Front. Cell. Infect. Microbiol.

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Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib. In this study, a 3D-QSAR model was built for SYK based on known inhibitor IC50 values. The best pharmacophore model was then used as a 3D query to screen a drug-like database to retrieve hits with novel chemical scaffolds. The obtained compounds were subjected to binding affinity prediction using the molecular docking approach, and the results were subsequently validated using molecular dynamics (MD) simulations. The simulated compounds were ranked according to binding free energy (ΔG), and the binding affinity was compared with fostamatinib. The binding mode analysis of selected compounds revealed that the hit compounds form hydrogen bond interactions with hinge region residue Ala451, glycine-rich loop residue Lys375, Ser379, and DFG motif Asp512. Identified hits were also observed to form a desirable interaction with Pro455 and Asn457, the rare feature observed in SYK inhibitors. Therefore, we argue that identified hit compounds ZINC98363745, ZINC98365358, ZINC98364133, and ZINC08789982 may help in drug design against SYK.

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Section: Introductionmentioning

confidence: 99%

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors

Kumar

Parate

Danishuddin

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Compounds play an important role in nature and have a number of biological effects, including antitumors. [16][17][18], antibacterial [19], antimicrobial [20], anti-viability [21], antiinflammatory [22], Syk inhibitor [23], antiviral [24], antiproliferative [25] and anticandidal activity [26].…”

Section: Introductionmentioning

confidence: 99%

In vivo Biochemical Evaluation of Some Synthesize Thiazole Derivatives Containing Coumarin Moiety as Antioxidant and Antitumor Agents

Mohammed

Barakat

Gad

et al. 2019

AJRB

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Background: Coumarin and thiazole derivatives have been used traditionally for many centuries. Because they have anti-tumor, antioxidant activities, and induced apoptosis. Aim: The present study aims to investigate the in vivo antitumor, and antioxidant activities of potassium salt of 5-(4 -chlorophenyl)-2-[(7-hydroxy coumarin-3-ylethylidene) acetyl hydrazine]-1,3 thiazole (5a) and 5-(4 -chlorophenyl)-2-[(8-hydroxy coumarin-3-ylethylidene) acetyl hydrazine]-1,3 thiazole (5b). Materials and Methods: Toxicity has been determined for the synthesized compound. Anti-cancer and anti-oxidant activities were studied through the evaluation of tumor cell viability, lifespan prolongation and antioxidant estimation. Results: Doses of up to 500 mg/kg showed good protection in 5a and 5b compounds. Results of in vivo anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells for the compounds studied showed a significant reduction in the volume and number of ascites. And increased in life span. In therapeutic and preventive groups, compounds 5a and 5b have anti-oxidant properties by a significant decrease in malondialdehyde and significant increased catalase and GSH. Also, compounds 5a and 5b induced apoptosis by increase Caspase-3 and BCL-2 associated protein (BAX), Compared to the group of positive controls. Conclusion: It was concluded that compounds 5a and 5b have a potent antitumor and antioxidant activity against Ehrlich ascites carcinoma in mice.

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“…Sci. 2016, 6,8 7/10 12 h. After the reaction was complete, the solution was added 20 mL CH2Cl2. Combined organic layers were washed with dilute hydrochloric acid (20 mL), saturated Na2CO3 solution (20 mL) and saturated NaCl solution (20 mL) respectively, dried with anhydrous Na2SO4.…”

Section: Synthesis Of Target Compounds (8a-g)mentioning

confidence: 99%

“…Sci. 2016, 6,8 6/10 thorough stirring, the mixture was filtered to get the white solid, which was washed with CH2Cl2 (10 mL) and distilled water (10 mL) to obtain 7 (Scheme 4). …”

Section: Synthesis Of Target Compounds (7a-f)mentioning

confidence: 99%

“…Substituted thiazole compounds play an important role in nature and have a diverse range of biological effects such as antitumor [1][2][3] antibacterial [4], antimicrobial [5], anti-viability [6], anti-inflammatory [7], Syk inhibitor [8], antiviral [9], antiproliferative [10], and anticandidal activity [11]. In past decades, amide containing heterocycles are reported as a class of compounds displaying extensive biological activities, which consist of a large number of natural and synthetic products and are extremely versatile building blocks for the manufacture of bioactive compounds in pharmaceutical drug design and agrochemical industry [12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Anticancer Activity of Novel Thiazole-5-Carboxamide Derivatives

Cai

Liu

et al. 2016

Applied Sciences

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A series of novel 2-phenyl-4-trifluoromethyl thiazole-5-carboxamide derivatives have been synthesized and evaluated for their anticancer activity against A-549, Bel7402, and HCT-8 cell lines. Among the tested compounds, highest activity (48%) was achieved with the 4-chloro-2-methylphenyl amido substituted thiazole containing the 2-chlorophenyl group on the two position of the heterocyclic ring. Other structurally similar compounds displayed moderate activity. The key intermediates have been fully characterized.

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Orally bioavailable Syk inhibitors with activity in a rat PK/PD model

Cited by 7 publications

References 32 publications

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors

In vivo Biochemical Evaluation of Some Synthesize Thiazole Derivatives Containing Coumarin Moiety as Antioxidant and Antitumor Agents

Synthesis and Anticancer Activity of Novel Thiazole-5-Carboxamide Derivatives

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