Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme

详细信息    查看全文

• 作者：Kevin D. Rynearson^a ; Ronald N. Buckle^b ; Keith D. Barnes^b ; R. Jason Herr^b ; Nicholas J. Mayhew^b ; William D. Paquette^b ; Samuel A. Sakwa^b ; Phuong D. Nguyen^a ; Graham Johnson^c ; Rudolph E. Tanzi^d ; Steven L. Wagner^a ; ^{slwagner@ucsd.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Alzheimer&rsquo ; s disease ; γ-Secretase modulators ; Aminothiazoles
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：26
• 期：16
• 页码：3928-3937
• 全文大小：3184 K

文摘

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.