Design, Synthesis, and Development of pyrazolo[1,5-<i>a</i>]pyrimidine Derivatives as a Novel Series of Selective PI3K<i>δ</i> Inhibitors: Part I-Indole Derivatives

• Main Authors: Mariola Stypik (Author), Marcin Zagozda (Author), Stanisław Michałek (Author), Barbara Dymek (Author), Daria Zdżalik-Bielecka (Author), Maciej Dziachan (Author), Nina Orłowska (Author), Paweł Gunerka (Author), Paweł Turowski (Author), Joanna Hucz-Kalitowska (Author), Aleksandra Stańczak (Author), Paulina Stańczak (Author), Krzysztof Mulewski (Author), Damian Smuga (Author), Filip Stefaniak (Author), Lidia Gurba-Bryśkiewicz (Author), Arkadiusz Leniak (Author), Zbigniew Ochal (Author), Mateusz Mach (Author), Karolina Dzwonek (Author), Monika Lamparska-Przybysz (Author), Krzysztof Dubiel (Author), Maciej Wieczorek (Author)
• Format: Book
• Published: MDPI AG, 2022-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Phosphoinositide 3-kinase <i>δ</i> (PI3K<i>δ</i>), a member of the class I PI3K family, is an essential signaling biomolecule that regulates the differentiation, proliferation, migration, and survival of immune cells. The overactivity of this protein causes cellular dysfunctions in many human disorders, for example, inflammatory and autoimmune diseases, including asthma or chronic obstructive pulmonary disease (COPD). In this work, we designed and synthesized a new library of small-molecule inhibitors based on indol-4-yl-pyrazolo[1,5-<i>a</i>]pyrimidine with IC₅₀ values in the low nanomolar range and high selectivity against the PI3K<i>δ</i> isoform. CPL302253 (<b>54</b>), the most potent compound of all the structures obtained, with IC₅₀ = 2.8 nM, is a potential future candidate for clinical development as an inhaled drug to prevent asthma.

Item Description

10.3390/ph15080949
1424-8247