Phosphodiesterases (PDE) are metalloproteins that catalyze the hydrolysis of the cyclic nucleotides - cAMP and/or cGMP. PDEs are of several types and are distributed across the various tissues in humans. PDE 2A is a dual substrate type of phosphodiesterase that is highly expressed in the brain regions responsible for cognitive functions. They are known to play key roles in the regulating the concentration of the second messenger cGMP in the brain. PDE2A inhibition has therefore been implied in curing brain related diseases such as schizophrenia. This seminar seeks to use TAK-915, a PDE 2A inhibitor currently undergoing phase I clinical trials, as a model to explore the design of small molecule inhibitors for PDE 2A.
Selected References
Mikami,S., Nakamura,S., Ashizawa, T., Nomura, I., Kawasaki, M., Sasaki, S., Oki, H., Kokubo, H., Hoffman, I.D., Zou, H., Uchiyama, N., Nakashima, K., Kamiguchi, N., Imada, H., Suzuki, N., Iwashita, H., Taniguchi, T. Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders. J. Med. Chem. 2017, 60(18), 7677-7702
Gomez, L.; Massari, M.E.; Vickers, T.; Freestone, G.; Vernier, W.; Ly, K.; Xu, R.; McCarrick, M.; Marrone, T.; Metz, M.; Yan, Y. G.; Yoder, Z. W.; Lemus, R.; Broadbent, N. J.; Barido, R.; Warren, N.; Schmelzer, K.; Neul, D.; Lee, D.; Andersen, C.B.; Sebring, K.; Aertgeerts, K.; Zhou, X.; Tabatabaei, A.; Peters, M.; Breitenbucher, J. G. Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2A) Inhibitors for the Treatment of Memory Disorders. J. Med. Chem., 2017, 60 (5), 2037–2051
Zhang, C.; Feng, L.; Huang, Y.; Wu, D.; Li, Z.; Zhou, Q.; Wu, Y.; Luo, H. Discovery of Novel Phosphodiesterase-2A Inhibitors by Structure-Based Virtual Screening, Structural Optimization, and Bioassay. J. Chem. Inf. Model., 2017, 57 (2), 355–364.
Zhu, J.; Yang, Q.; Dai, D.; Huang, Q. X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity. J. Am. Chem. Soc. 2013, 135 (32), 11708–11711