8BPY

X-RAY STRUCTURE OF PDE9A IN COMPLEX WITH Inhibitor 13A

8BPY の概要

• エントリーDOI: 10.2210/pdb8bpy/pdb
• 分子名称: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: pde9a, inhibitor, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75025.89

構造登録者

Steuber, H. (登録日: 2022-11-18, 公開日: 2022-12-28, 最終更新日: 2024-10-16)

主引用文献

Meibom, D.,Micus, S.,Andreevski, A.L.,Anlauf, S.,Bogner, P.,von Buehler, C.J.,Dieskau, A.P.,Dreher, J.,Eitner, F.,Fliegner, D.,Follmann, M.,Gericke, K.M.,Maassen, S.,Meyer, J.,Schlemmer, K.H.,Steuber, H.,Tersteegen, A.,Wunder, F.
BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor.
J.Med.Chem., 65:16420-16431, 2022

PubMed Abstract: Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit. Key aspect of the optimization was a switch in metabolism of our lead structures from glucuronidation to oxidation. The switch proved being essential for the identification of compounds with improved pharmacokinetic profiles. By studying a tool compound in a transverse aortic constriction mouse model, we were able to substantiate the relevance of PDE9A inhibition in heart diseases.

PubMed: 36475653
DOI: 10.1021/acs.jmedchem.2c01267

実験手法

X-RAY DIFFRACTION (3.3 Å)