5AXQ

Crystal structure of the catalytic domain of PDE10A complexed with highly potent and brain-penetrant PDE10A Inhibitor with 2-oxindole scaffold

Summary for 5AXQ

• Entry DOI: 10.2210/pdb5axq/pdb
• Related: 5AXP
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, MAGNESIUM ION, ZINC ION, ... (6 entities in total)
• Functional Keywords: hydrolase/hydrolase inhibitor, hydrolase-hydrolase inhibitor complex
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9Y233
• Total number of polymer chains: 2
• Total formula weight: 78905.55

Authors

Oki, H.,Zama, Y. (deposition date: 2015-07-31, release date: 2015-11-11, Last modification date: 2024-03-20)

Primary citation

Yoshikawa, M.,Kamisaki, H.,Kunitomo, J.,Oki, H.,Kokubo, H.,Suzuki, A.,Ikemoto, T.,Nakashima, K.,Kamiguchi, N.,Harada, A.,Kimura, H.,Taniguchi, T.
Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor
Bioorg.Med.Chem., 23:7138-7149, 2015

PubMed Abstract: Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice.

PubMed: 26494583
DOI: 10.1016/j.bmc.2015.10.002

Experimental method

X-RAY DIFFRACTION (1.77 Å)