5B25

Crystal structure of human PDE1B with inhibitor 3

Summary for 5B25

• Entry DOI: 10.2210/pdb5b25/pdb
• Descriptor: Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B, ZINC ION, MAGNESIUM ION, ... (7 entities in total)
• Functional Keywords: hydrolase, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q01064
• Total number of polymer chains: 4
• Total formula weight: 158383.14

Authors

Ida, K.,Lane, W.,Snell, G.,Sogabe, S. (deposition date: 2016-01-07, release date: 2016-02-03, Last modification date: 2023-11-08)

Primary citation

Li, P.,Zheng, H.,Zhao, J.,Zhang, L.,Yao, W.,Zhu, H.,Beard, J.D.,Ida, K.,Lane, W.,Snell, G.,Sogabe, S.,Heyser, C.J.,Snyder, G.L.,Hendrick, J.P.,Vanover, K.E.,Davis, R.E.,Wennogle, L.P.
Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases
J.Med.Chem., 59:1149-1164, 2016

PubMed Abstract: A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer's disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders.

PubMed: 26789933
DOI: 10.1021/acs.jmedchem.5b01751

Experimental method

X-RAY DIFFRACTION (1.9 Å)