Design, Synthesis, and Development of Pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part II—Benzimidazole Derivatives

• DOI: 10.3390/ph15080927
• Publication Date: 2022-07-28T07:21:16Z
• Authors: Mariola Stypik; Stanisław Michałek; Nina Orłowska; Marcin Zagozda; Maciej Dziachan; Martyna Banach; Paweł Turowski; Paweł Gunerka; Daria Zdżalik-Bie...; Aleksandra Stańczak; Urszula Kędzierska; Krzysztof Mulewski; Damian Smuga; Wioleta Maruszak; Lidia Gurba-Bryśk...; Arkadiusz Leniak; Wojciech Pietruś; Zbigniew Ochal; Mateusz Mach; Beata Zygmunt; Jerzy Pieczykolan; Krzysztof Dubiel; Maciej Wieczorek
• Keywords: Benzimidazole; IC50

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to high expression these proteins many human cells and their involvement metabolism regulation, normal embryogenesis, maintaining glucose homeostasis, inhibition PI3K (especially first class which contains four subunits: α, β, γ, δ) considered be a promising therapeutic strategy for treatment inflammatory autoimmune diseases systemic lupus erythematosus (SLE) multiple sclerosis. In this work, we synthesized library benzimidazole derivatives pyrazolo[1,5-a]pyrimidine representing collection new, potent, active, selective inhibitors PI3Kδ, displaying IC50 values ranging from 1.892 0.018 μM. Among all compounds obtained, CPL302415 (6) showed highest activity (IC50 value 18 nM PI3Kδ), good selectivity (for PI3Kδ relative other isoforms: PI3Kα/δ = 79; PI3Kβ/δ 1415; PI3Kγ/δ 939), physicochemical properties. As lead compound on relatively large scale, structure potential future candidate clinical trials SLE treatment.