Approaching the active conformation of 1,3-diaminopyrimidine based covalent inhibitors of Bruton’s tyrosine kinase for treatment of Rheumatoid arthritis

Huang, Zhenhua; Zhang, Qian; Yan, Lianzhong; Zhong, Guizhen; Zhang, Linqi; Tan, Xiaojuan; Wang, Yanli

doi:10.1016/j.bmcl.2016.03.011

Cited by 13 publications

(6 citation statements)

References 11 publications

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“…Reductive amination was used as a convenient method for the synthesis of derivatives 2 and 3 from commercially available pyrimidine 1 . Thus, we changed the typical reaction sequence to N -methyl pyrimidine 2 , where alkylation usually precedes to chlorination step [21]. In the case of 3 , we optimized reaction conditions using 2,2-dimethoxypropane and sodium tri-acetoxyborohydride [22].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and structural optimization of 2,7,9-trisubstituted purin-8-ones as FLT3-ITD inhibitors

Tomanová

Kozlanská

Jorda

et al. 2022

Preprint

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Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availa-bility of newly approved kinase inhibitors. Various strategies to avoid reduced efficacy of ther-apy are explored including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here structure-activity relation-ship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase and the isopropyl group at position 7 increased substantially the selec-tivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses including suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo.

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Section: Resultsmentioning

confidence: 99%

Synthesis and structural optimization of 2,7,9-trisubstituted purin-8-ones as FLT3-ITD inhibitors

Tomanová

Kozlanská

Jorda

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Reductive amination was used as a convenient method for the synthesis of derivatives 2 and 3 from commercially available pyrimidine 1. Thus, we changed the typical reaction sequence to N-methyl pyrimidine 2, where alkylation usually precedes to chlorination step [21]. In the case of 3, we optimized reaction conditions using 2,2-dimethoxypropane and sodium triacetoxyborohydride [22].…”

Section: Chemistrymentioning

confidence: 99%

“…Finally, the vessel was cooled to approximately 40 • C with compressed air (cooling time ∼1 min). Intermediates 2, 3, 4a, 4b, 5c, 8a-b, 9c-e, 9j, and 9l, 9p-o have been already reported [21,22,[32][33][34][35], for more information see Supplementary Information.…”

Section: General Informationmentioning

confidence: 99%

Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors

Tomanová

Kozlanská

Jorda

et al. 2022

IJMS

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Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for the survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here the structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase, and the isopropyl group at position 7 substantially increased the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo.

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“…2-amino-7,9-dihydro-8Hpurin-8-one is a compound that has demonstrated its efficacy in the treatment of several diseases (Figure 1). In particular, it has been identified as a potential inhibitor of Janus kinases (JAKs) and as an anticancer agent [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Computer-Aided Drug Design of Novel Derivatives of 2-Amino-7,9-dihydro-8H-purin-8-one as Potent Pan-Janus JAK3 Inhibitors

et al. 2023

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Rheumatoid arthritis (RA) remains one of the most prevalent autoimmune diseases worldwide. Janus kinase 3 (JAK3) is an essential enzyme for treating autoimmune diseases, including RA. Molecular modeling techniques play a crucial role in the search for new drugs by reducing time delays. In this study, the 3D-QSAR approach is employed to predict new JAK3 inhibitors. Two robust models, both field-based with R2 = 0.93, R = 0.96, and Q2 = 87, and atom-based with R2 = 0.94, R = 0.97, and Q2 = 86, yielded good results by identifying groups that may readily direct their interaction. A reliable pharmacophore model, DHRRR1, was provided in this work to enable the clear characterization of chemical features, leading to the design of 13 inhibitors with their pIC50 values. The DHRRR1 model yielded a validation result with a ROC value of 0.87. Five promising inhibitors were selected for further study based on an ADMET analysis of their pharmacokinetic properties and covalent docking (CovDock). Compared to the FDA-approved drug tofacitinib, the pharmaceutical features, binding affinity and stability of the inhibitors were analyzed through CovDock, 300 ns molecular dynamics simulations, free energy binding calculations and ADMET predictions. The results show that the inhibitors have strong binding affinity, stability and favorable pharmaceutical properties. The newly predicted molecules, as JAK3 inhibitors for the treatment of RA, are promising candidates for use as drugs.

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Approaching the active conformation of 1,3-diaminopyrimidine based covalent inhibitors of Bruton’s tyrosine kinase for treatment of Rheumatoid arthritis

Cited by 13 publications

References 11 publications

Synthesis and structural optimization of 2,7,9-trisubstituted purin-8-ones as FLT3-ITD inhibitors

Synthesis and structural optimization of 2,7,9-trisubstituted purin-8-ones as FLT3-ITD inhibitors

Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors

Computer-Aided Drug Design of Novel Derivatives of 2-Amino-7,9-dihydro-8H-purin-8-one as Potent Pan-Janus JAK3 Inhibitors

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