Young Wendy B, Barbosa James, Blomgren Peter, Bremer Meire C, Crawford James J, Dambach Donna, Eigenbrot Charles, Gallion Steve, Johnson Adam R, Kropf Jeffrey E, Lee Seung H, Liu Lichuan, Lubach Joseph W, Macaluso Jen, Maciejewski Pat, Mitchell Scott A, Ortwine Daniel F, Di Paolo Julie, Reif Karin, Scheerens Heleen, Schmitt Aaron, Wang Xiaojing, Wong Harvey, Xiong Jin-Ming, Xu Jianjun, Yu Christine, Zhao Zhongdong, Currie Kevin S
Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
Bioorg Med Chem Lett. 2016 Jan 15;26(2):575-579. doi: 10.1016/j.bmcl.2015.11.076. Epub 2015 Nov 24.
BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties.
布鲁顿酪氨酸激酶（BTK）抑制剂GDC-0834（1）在人体研究中被发现会迅速代谢，导致临床试验暂停。主要代谢途径是通过连接末端四氢苯并噻吩与中心连接芳环的无环酰胺键的裂解。构效关系（SAR）研究集中于减少该酰胺的代谢裂解，并确定了几个能提高稳定性的中心芳基连接取代基。然后将最有前景的取代芳基连接体引入优化的哒嗪酮骨架中，从而确定了先导类似物23，其具有更高的效力、代谢稳定性和临床前特性。
