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Design, synthesis and evaluation of a series of potential prodrugs of a Bruton's tyrosine kinase (BTK) inhibitor.

ABSTRACT: BTK has become a particularly attractive therapeutic target in autoimmune diseases and B-cell malignancies, making BTK inhibitors a valuable and important therapeutic option. We present the design, synthesis, and evaluation of a series of prodrugs of a BTK inhibitor with an insoluble 2,5-diaminopyrimidine structure. Tails containing different solubilizing groups were added to the parent molecule via an ester linkage. Prodrug 5a showed good aqueous solubility and could be efficiently converted to the parent in a human plasma stability study. The rational prodrug design was supported by molecular studies and a dramatically reduced BTK kinase-inhibitory potential. Taken together, the chemical, biological, and molecular studies suggest that prodrug derivatization of the 2,5-diaminopyrimidine scaffold could be a potential strategy for advancing this series of BTK inhibitors into the therapeutic arena.

SUBMITTER: Xiao ZP

PROVIDER: S-EPMC10031131 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Design, synthesis and evaluation of a series of potential prodrugs of a Bruton's tyrosine kinase (BTK) inhibitor.

Xiao Zhou-Peng ZP Liao Min M Huang Xue-Juan XJ Wang Yu-Tong YT Lan Xiao-Cui XC Wang Xue-Ying XY Li Xi-Tao XT

Frontiers in pharmacology 20230308

BTK has become a particularly attractive therapeutic target in autoimmune diseases and B-cell malignancies, making BTK inhibitors a valuable and important therapeutic option. We present the design, synthesis, and evaluation of a series of prodrugs of a BTK inhibitor with an insoluble 2,5-diaminopyrimidine structure. Tails containing different solubilizing groups were added to the parent molecule <i>via</i> an ester linkage. Prodrug <b>5a</b> showed good aqueous solubility and could be efficientl ...[more]

PMID: 36969836

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Project description:Clinical development of BTK kinase inhibitors for treating autoimmune diseases has lagged behind development of these drugs for treating cancers, due in part from concerns over the lack of selectivity and associated toxicity profiles of first generation drug candidates when used in the long term treatment of immune mediated diseases. Second generation BTK inhibitors have made great strides in limiting off-target activities for distantly related kinases, though they have had variable success at limiting cross-reactivity within the more closely related TEC family of kinases. We investigated the BTK specificity and toxicity profiles, drug properties, disease associated signaling pathways, clinical indications, and trial successes and failures for the 13 BTK inhibitor drug candidates tested in phase 2 or higher clinical trials representing 7 autoimmune and 2 inflammatory immune-mediated diseases. We focused on rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE) where the majority of BTK nonclinical and clinical studies have been reported, with additional information for pemphigus vulgaris (PV), Sjogren's disease (SJ), chronic spontaneous urticaria (CSU), graft versus host disease (GVHD), and asthma included where available. While improved BTK selectivity versus kinases outside the TEC family improved clinical toxicity profiles, less profile distinction was evident within the TEC family. Analysis of genetic associations of RA, MS, and SLE biomarkers with TEC family members revealed that BTK and TEC family members may not be drivers of disease. They are, however, mediators of signaling pathways associated with the pathophysiology of autoimmune diseases. BTK in particular may be associated with B cell and myeloid differentiation as well as autoantibody development implicated in immune mediated diseases. Successes in the clinic for treating RA, MS, PV, ITP, and GVHD, but not for SLE and SJ support the concept that BTK plays an important role in mediating pathogenic processes amenable to therapeutic intervention, depending on the disease. Based on the data collected in this study, we propose that current compound characteristics of BTK inhibitor drug candidates for the treatment of autoimmune diseases have achieved the selectivity, safety, and coverage requirements necessary to deliver therapeutic benefit.

Dataset Information

Design, synthesis and evaluation of a series of potential prodrugs of a Bruton's tyrosine kinase (BTK) inhibitor.

Publications

Design, synthesis and evaluation of a series of potential prodrugs of a Bruton's tyrosine kinase (BTK) inhibitor.

Similar Datasets

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