Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain [electronic resource] : Lead Optimization via Structure-Based Drug Design

• Ngôn ngữ: eng
• Ký hiệu phân loại: 611.5 Human anatomy, cytology, histology
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 857-861 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260833
• Chủ đề: 1. 60 applied life sciences; 2. Autotaxin; 3. Lpa; 4. Osteoarthritis; 5. Tool molecule

Tóm tắt

 In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC<
 sub>
 50<
 /sub>
  of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC<
 sub>
 50<
 /sub>
  = 2 nM), PK properties, and a robust PK/PD relationship.