4WN1

Crystal structure of PDE10A in complex with 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one

Summary for 4WN1

• Entry DOI: 10.2210/pdb4wn1/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase, complex, inhibitor, 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: 79814.77

Authors

Amano, Y.,Honbou, K. (deposition date: 2014-10-10, release date: 2014-12-31, Last modification date: 2023-12-27)

Primary citation

Hamaguchi, W.,Masuda, N.,Miyamoto, S.,Shiina, Y.,Kikuchi, S.,Mihara, T.,Moriguchi, H.,Fushiki, H.,Murakami, Y.,Amano, Y.,Honbou, K.,Hattori, K.
Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition.
Bioorg.Med.Chem., 23:297-313, 2015

PubMed Abstract: A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test.

PubMed: 25515954
DOI: 10.1016/j.bmc.2014.11.039

Experimental method

X-RAY DIFFRACTION (3.13 Å)