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

Phosphoinositide 3-kinase δ (PI3K δ ), 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- a ]pyrimidine with IC 50 values in the low nanomolar range and high selectivity against the PI3K δ isoform. CPL302253 ( 54 ), the most potent compound of all the structures obtained, with IC 50 = 2.8 nM, is a potential future candidate for clinical development as an inhaled drug to prevent asthma.