Goldberg Daniel R, De Lombaert Stéphane, Aiello Robert, Bourassa Patricia, Barucci Nicole, Zhang Qing, Paralkar Vishwas, Stein Adam J, Holt Melissa, Valentine Jim, Zavadoski William
Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
Karos Pharmaceuticals, 401 Winchester Ave., 5 Science Park, New Haven, CT 06511, United States.
Bioorg Med Chem Lett. 2017 Feb 1;27(3):413-419. doi: 10.1016/j.bmcl.2016.12.053. Epub 2016 Dec 23.
As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. This effort led to new TPH1 inhibitors with in vivo efficacy when dosed as their corresponding ethyl ester prodrugs. In particular, 15b (KAR5585), the prodrug of the potent TPH1 inhibitor 15a (KAR5417), showed robust reduction of intestinal serotonin (5-HT) levels in mice. Furthermore, oral administration of 15b generated high and sustained systemic exposure of the active parent 15a in rats and dogs. KAR5585 was selected for further pharmacological evaluation in disease models associated with a dysfunctional peripheral 5-HT system.
作为我们基于螺环脯氨酸的色氨酸羟化酶1（TPH1）抑制剂先导物发现的后续研究，我们描述了该骨架的优化过程。通过结合X射线共晶体结构导向设计和体内筛选，在抑制剂的亲脂区域鉴定出了新的取代基。这项工作产生了新的TPH1抑制剂，当以其相应的乙酯前药形式给药时具有体内疗效。特别是，强效TPH1抑制剂15a（KAR5417）的前药15b（KAR5585）在小鼠中显示出肠道5-羟色胺（5-HT）水平的显著降低。此外，口服15b在大鼠和犬中产生了活性母体15a的高且持续的全身暴露。KAR5585被选择用于在与外周5-HT系统功能失调相关的疾病模型中进行进一步的药理学评估。
