Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 619.45 Experimental medicine
• Thông tin xuất bản: Bethesda, Md. : Oak Ridge, Tenn. : National Institutes of Health (U.S.) ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2019
• Mô tả vật lý: Size: p. 4884-4901 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260030
• Chủ đề: 1. 60 applied life sciences; 2. High-performance liquid chromatography; 3. Inhibitors; 4. Peptides and proteins; 5. Rodent models; 6. Selectivity

Tóm tắt

Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.