Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Bioorg Med Chem. 2019 Mar 15;27(6):1056-1064. doi: 10.1016/j.bmc.2019.02.001. Epub 2019 Feb 1.
Chemical optimization of the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (THPP) scaffold was conducted with a focus on cellular potency while maintaining high selectivity against PI3K isoforms. Compound 11f was identified as a potent, highly selective and orally available PI3Kδ inhibitor. In addition, 11f exhibited efficacy in an in vivo antibody production model. The desirable drug-like properties and in vivo efficacy of 11f suggest its potential as a drug candidate for the treatment of autoimmune diseases and leukocyte malignancies.
对 5,6,7,8-四氢吡啶并[4,3-d]嘧啶（THPP）骨架进行了化学优化，重点关注细胞效力，同时保持对 PI3K 同工型的高选择性。化合物 11f 被鉴定为一种有效、高选择性且可口服的 PI3Kδ 抑制剂。此外，11f 在体内抗体产生模型中表现出疗效。11f 具有良好的类药性和体内疗效，表明其有可能成为治疗自身免疫性疾病和白细胞恶性肿瘤的候选药物。
