Chemical optimization of pyrazolopyridine 1, focused on cellular potency, isoform selectivity and microsomal stability, led to the discovery of the potent, selective and orally available PI3Kδ inhibitor 5d. On the basis of its desirable potency, selectivity and pharmacokinetic profiles, 5d was tested in the trinitrophenylated aminoethylcarboxymethyl-Ficoll (TNP-Ficoll)-induced antibody production model, and showed higher antibody inhibition than a 4-fold oral dose of the starting compound 1. These excellent results suggest that 5d is a potential candidate for further studies in the treatment of autoimmune diseases and leukocyte malignancies.

吡唑并吡啶1的化学优化集中在细胞效价，同工型选择性和微粒体稳定性上，导致发现了有效的，选择性的和口服的PI3Kδ抑制剂5d。在其理想的效价，选择性和药代动力学特征的基础上，5D在三硝基苯aminoethylcarboxymethyl聚蔗糖（TNP-Ficoll）的溶液诱导的抗体的产生模型中测试，并显示出更高的抗体抑制比4倍起始化合物的口服剂量1。这些优异的结果表明5d是治疗自身免疫性疾病和白细胞恶性肿瘤的潜在候选药物。