Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3Kδ Immunomodulators

The
approvals of idelalisib and duvelisib have validated PI3Kδ
inhibitors for the treatment for hematological malignancies driven
by the PI3K/AKT pathway. Our program led to the identification of
structurally distinct heterocycloalkyl purine inhibitors with excellent
isoform and kinome selectivity; however, they had high projected human
doses. Improved ligand contacts gave potency enhancements, while replacement
of metabolic liabilities led to extended half-lives in preclinical
species, affording PI3Kδ inhibitors with low once-daily predicted
human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice with 30
and 100 mg/kg/day of 3c (MSD-496486311) led to a 70%
reduction in Foxp3-expressing regulatory T cells as observed through
bioluminescence imaging with luciferin, consistent with the role of
PI3K/AKT signaling in Treg cell proliferation. As a model for allergic
rhinitis and asthma, treatment of ovalbumin-challenged Brown Norway
rats with 0.3 to 30 mg/kg/day of 3c gave a dose-dependent
reduction in pulmonary bronchoalveolar lavage inflammation eosinophil
cell count.