3UUO

The discovery of potent, selectivity, and orally bioavailable pyrozoloquinolines as PDE10 inhibitors for the treatment of Schizophrenia

Summary for 3UUO

• Entry DOI: 10.2210/pdb3uuo/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, 6-methoxy-3,8-dimethyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]quinoline, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: inhibitor complex, hydrolase, zn binding, mg binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9Y233
• Total number of polymer chains: 2
• Total formula weight: 79007.96

Authors

Ho, G.D.,Yang, S.,Smotryski, J.,Bercovici, A.,Nechuta, T.,Smith, E.M.,McElroy, W.,Tan, Z.,Tulshian, D.,Mckittrick, B.,Greenlee, W.J.,Hruza, A.,Xiao, L.,Rindgen, D.,Guzzi, M.,Zhang, X.,Bleickardt, C.,Mullins, D.,Hodgson, R. (deposition date: 2011-11-28, release date: 2012-01-25, Last modification date: 2024-02-28)

Primary citation

Ho, G.D.,Yang, S.W.,Smotryski, J.,Bercovici, A.,Nechuta, T.,Smith, E.M.,McElroy, W.,Tan, Z.,Tulshian, D.,McKittrick, B.,Greenlee, W.J.,Hruza, A.,Xiao, L.,Rindgen, D.,Mullins, D.,Guzzi, M.,Zhang, X.,Bleickardt, C.,Hodgson, R.
The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia.
Bioorg.Med.Chem.Lett., 22:1019-1022, 2012

PubMed Abstract: High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a ∼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.

PubMed: 22222034
DOI: 10.1016/j.bmcl.2011.11.127

Experimental method

X-RAY DIFFRACTION (2.11 Å)