APD371的发现：一种用于治疗慢性疼痛的高效且选择性的CB激动剂的鉴定。
Discovery of APD371: Identification of a Highly Potent and Selective CB Agonist for the Treatment of Chronic Pain.
作者信息
Han Sangdon, Thoresen Lars, Jung Jae-Kyu, Zhu Xiuwen, Thatte Jayant, Solomon Michelle, Gaidarov Ibragim, Unett David J, Yoon Woo Hyun, Barden Jeremy, Sadeque Abu, Usmani Amin, Chen Chuan, Semple Graeme, Grottick Andrew J, Al-Shamma Hussein, Christopher Ronald, Jones Robert M
机构信息
Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
出版信息
ACS Med Chem Lett. 2017 Nov 30;8(12):1309-1313. doi: 10.1021/acsmedchemlett.7b00396. eCollection 2017 Dec 14.
Abstract
The discovery of a novel, selective and fully efficacious CB agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB receptor to avoid tachyphylaxis. Based on its overall favorable preclinical profile, (APD371) was selected for further development for the treatment of pain.
摘要
本文描述了一种新型、选择性且完全有效的CB激动剂的发现，其具有令人满意的药代动力学和药物性质。化合物在口服给药后对骨关节炎疼痛的大鼠模型有效，并且与吗啡不同，在为期5天的亚慢性治疗模式中维持其镇痛效果。这些数据与我们的假设一致，即CB受体的有效内化和再循环需要完全激动剂效力以避免快速耐受性。基于其总体良好的临床前特征，选择（APD371）进行疼痛治疗的进一步开发。
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