科研之友
微信
新浪微博
Facebook
分享链接
摘要
PI3K delta and PI3K gamma regulate immune cell signaling. Selective PI3K delta or PI3K gamma inhibitors and dual PI3K delta/gamma inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazoloI3,4-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 PI3K delta inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3K delta at the concentration of 1 mu M, with the 1050 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3K delta (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3K delta over beta and gamma, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3K delta/gamma inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3K delta and PI3K gamma, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3K delta over PI3K alpha and PI3K beta. In agreement with their remarkable PI3K delta inhibitory activity, compounds 10d and 10e showed high anti proliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3K delta/gamma inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%.
