Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors

PI3Kδ and PI3Kγ regulate immune cell signaling. Selective PI3Kδ or PI3Kγ inhibitors and dual PI3Kδ/γ inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazolo[3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3Kδ inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3Kδ at the concentration of 1 μM, with the IC₅₀ values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5-yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3Kδ (IC₅₀ = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3Kδ over PI3Kα, β and γ, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3Kδ/γ inhibitor 10e with IC₅₀ values of 8.4 nM and 62 nM against PI3Kδ and PI3Kγ, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3Kδ over PI3Kα and PI3Kβ. In agreement with their remarkable PI3Kδ inhibitory activity, compounds 10d and 10e showed high antiproliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3Kδ/γ inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%.

B-Cell inhibition; PI3K isoform selectivity; PI3Kδ inhibitor; PI3Kδ/γ inhibitors; Quinazolinones.