Rynearson Kevin D, Buckle Ronald N, Barnes Keith D, Herr R Jason, Mayhew Nicholas J, Paquette William D, Sakwa Samuel A, Nguyen Phuong D, Johnson Graham, Tanzi Rudolph E, Wagner Steven L
Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive MC 0624, La Jolla, CA 92093-0624, United States.
Department of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
Bioorg Med Chem Lett. 2016 Aug 15;26(16):3928-37. doi: 10.1016/j.bmcl.2016.07.011. Epub 2016 Jul 6.
The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aβ42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds.
本文描述了一系列新型氨基噻唑衍生的γ-分泌酶调节剂的设计与构建。为了使活性与良好的类药性质相匹配，对先导化合物1末端苯基D环进行了杂环取代。γ-分泌酶调节剂28在体外对Aβ42具有良好的抑制活性，并且在药物代谢动力学（ADME）和物理化学性质方面有显著改善，包括水溶性。化合物28在小鼠体内的药代动力学评估显示出良好的脑渗透性，以及良好的清除率、半衰期和分布容积，这些共同支持了这类化合物的持续研发。
