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开发了穿透大脑的皮里达松酸激酶激活剂

Rajendra Tangallapally¹, Chitra Subramanian², Mi-Kyung Yun³

¹Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS1000, Memphis, Tennessee 38105, United States.

Journal of medicinal chemistry

|August 13, 2024

概括

研究人员优化了氨酸激酶 (PANK) 激活剂,以提高协酶A (CoA) 水平. 这导致了神经退行性疾病和代谢障碍的新疗法,其中一种化合物进入临床试验.

科学领域:

生物化学生物化学
神经科学是一个神经科学.
药理学药理学是指药理学的学科.

背景情况:

潘托酸酶 (PANK) 酶在人类中启动协酶A (CoA) 生物合成.
乙-CoA水平以全质调节PANK,控制CoA的生产速度.
PANK激活剂对泛氨酸激酶相关的神经退行症 (PKAN) 和酸性病症具有治疗潜力.

研究的目的:

通过结构导向设计优化 PANK 化激活剂.
增强细胞CoA激活,代谢稳定性和可溶性.
确定具有改善药理动力学和大脑CoA升高的临床前化合物.

主要方法:

结构引导的设计用于PANK激活器优化.
评估细胞CoA激活,代谢稳定性和可溶性.
药物动力学概况和大脑CoA水平的评估.

主要成果:

优先考虑三个晚期临床前PANK调节器.
药物动力学概况的明显改善.
通过化合物获得的大脑CoA水平的显著增加.

结论:

优化的PANK激活剂在治疗PKAN和酸血症方面表现有前途.
化合物22 (BBP-671) 已进入临床试验阶段.
结构-活动关系研究成功指导了有效的PANK调节器的开发.

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