Yue Eddy W, Li Yun-Long, Douty Brent, He Chunhong, Mei Song, Wayland Brian, Maduskuie Thomas, Falahatpisheh Nikoo, Sparks Richard B, Polam Padmaja, Zhu Wenyu, Glenn Joseph, Feng Hao, Zhang Ke, Li Yanlong, He Xin, Katiyar Kamna, Covington Maryanne, Feldman Patricia, Shin Niu, Wang Kathy He, Diamond Sharon, Li Yu, Koblish Holly K, Hall Leslie, Scherle Peggy, Yeleswaram Swamy, Xue Chu-Biao, Metcalf Brian, Combs Andrew P, Yao Wenqing
Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
ACS Med Chem Lett. 2019 Oct 17;10(11):1554-1560. doi: 10.1021/acsmedchemlett.9b00334. eCollection 2019 Nov 14.
A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (, parsaclisib). The unique structure of contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (), duvelisib (), and INCB040093 (, dezapelisib). Parsaclisib () is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.
一项专注于鉴定磷酸肌醇3-激酶δ（PI3Kδ）结构多样候选物的药物化学研究，导致了临床候选药物INCB050465（帕萨克利西布）的发现。[该药物]独特的结构包含一个吡唑并嘧啶铰链结合剂，取代了其他PI3Kδ抑制剂（如idelalisib（依地利昔布）、duvelisib（度维利西布）和INCB040093（德扎利西布））中存在的嘌呤基序。帕萨克利西布是一种强效且高度选择性的PI3Kδ抑制剂，具有类药物的吸收、分布、代谢和排泄特性，在大鼠、狗和猴子身上进行的药代动力学研究以及在小鼠Pfeiffer异种移植模型中进行的药效学和疗效研究表明，其体内表现优异。
