Yang Zhi-Qiang, Schlegel Kelly-Ann S, Shu Youheng, Reger Thomas S, Cube Rowena, Mattern Christa, Coleman Paul J, Small Jim, Hartman George D, Ballard Jeanine, Tang Cuyue, Kuo Yuhsin, Prueksaritanont Thomayant, Nuss Cindy E, Doran Scott, Fox Steve V, Garson Susan L, Li Yuxing, Kraus Richard L, Uebele Victor N, Taylor Adekemi B, Zeng Wei, Fang Wei, Chavez-Eng Cynthia, Troyer Matthew D, Luk Julie Ann, Laethem Tine, Cook William O, Renger John J, Barrow James C
Departments of Medicinal Chemistry.
Drug Metabolism and Pharmacokinetics.
ACS Med Chem Lett. 2010 Aug 24;1(9):504-9. doi: 10.1021/ml100170e. eCollection 2010 Dec 9.
A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetry model, favorable pharmacokinetic properties, and excellent preclinical safety. TTA-A8 recently progressed into human clinical trials, and in line with our predictions, preliminary studies (n = 12) with a 20 mg oral dose afforded a high C max of 1.82 ± 0.274 μM with an apparent terminal half-life of 3.0 ± 1.1 h.
已通过体外和体内试验鉴定并评估了一种新型的苯乙酰胺类短效T型钙通道拮抗剂。苯乙酰胺4位的杂环取代产生了强效且选择性的拮抗剂，这些拮抗剂在临床前物种中表现出所需的短血浆半衰期。先导化合物TTA-A8成为一种具有出色体内疗效的化合物，这体现在其在脑电图遥测模型中对大鼠睡眠结构的显著调节、良好的药代动力学特性以及出色的临床前安全性。TTA-A8最近进入了人体临床试验，与我们的预测一致，20毫克口服剂量的初步研究（n = 12）产生了1.82±0.274μM的高Cmax，表观末端半衰期为3.0±1.1小时。
