Bandarage Upul K, Aronov Alex M, Cao Jingrong, Come Jon H, Cottrell Kevin M, Davies Robert J, Giroux Simon, Jacobs Marc, Mahajan Sudipta, Messersmith David, Moody Cameron S, Swett Rebecca, Xu Jinwang
Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States.
ACS Med Chem Lett. 2020 Dec 18;12(1):129-135. doi: 10.1021/acsmedchemlett.0c00573. eCollection 2021 Jan 14.
Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that control a wide variety of cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. PI3Kγ plays a critical role in mediating leukocyte chemotaxis as well as mast cell degranulation, making it a potentially interesting target for autoimmune and inflammatory diseases. We previously disclosed a novel series of PI3Kγ inhibitors derived from a benzothiazole core. The truncation of the benzothiazole core led to the discovery of a structurally diverse alkynyl thiazole series which displayed high PI3Kγ potency and subtype selectivity. Further medicinal chemistry optimization of the alkynyl thiazole series led to identification of compounds such as and , highly potent, subtype selective, and CNS penetrant PI3Kγ inhibitors. Compound showed robust inhibition of PI3Kγ mediated neutrophil migration .
磷脂酰肌醇3-激酶（PI3Ks）是一类酶，可控制多种细胞功能，如细胞生长、增殖、分化、运动、存活和细胞内运输。PI3Kγ在介导白细胞趋化性以及肥大细胞脱颗粒中起关键作用，使其成为自身免疫性疾病和炎症性疾病潜在的有趣靶点。我们之前公开了一系列源自苯并噻唑核心的新型PI3Kγ抑制剂。苯并噻唑核心的截短导致发现了结构多样的炔基噻唑系列，该系列显示出高PI3Kγ效力和亚型选择性。对炔基噻唑系列进行进一步的药物化学优化，得到了如化合物 和 等高效、亚型选择性且具有中枢神经系统渗透性的PI3Kγ抑制剂。化合物 对PI3Kγ介导的中性粒细胞迁移表现出强烈抑制作用。
