8BPY

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

Summary for 8BPY

• Entry DOI: 10.2210/pdb8bpy/pdb
• Descriptor: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde9a, inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 75025.89

Authors

Steuber, H. (deposition date: 2022-11-18, release date: 2022-12-28, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.3 Å)