Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach

详细信息    查看全文

• 作者：Jonathan E. Wilson ; Ravi Kurukulasuriya ; Mikhail Reibarkh ; Maud Reiter ; Aaron Zwicker ; Kake Zhao ; Fengqi Zhang ; Rajan Anand ; Vincent J. Colandrea ; Anne-Marie Cumiskey ; Alejandro Crespo ; Ruth A. Duffy ; Beth Ann Murphy ; Kaushik Mitra ; Douglas G. Johns ; Joseph L. Duffy ; Petr Vachal
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：261-265
• 全文大小：419K
• ISSN：1948-5875

文摘

Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from ¹H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK–PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.