4TPM

Crystal structure of 2-(3-alkoxy-1-azetidinyl) quinolines as PDE10A Inhibitors

Summary for 4TPM

• Entry DOI: 10.2210/pdb4tpm/pdb
• Related: 4TPP
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, SULFATE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: pde10a, quinolines, 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: 83632.34

Authors

Chmait, S. (deposition date: 2014-06-08, release date: 2014-12-17, Last modification date: 2024-11-13)

Primary citation

Rzasa, R.M.,Frohn, M.J.,Andrews, K.L.,Chmait, S.,Chen, N.,Clarine, J.G.,Davis, C.,Eastwood, H.A.,Horne, D.B.,Hu, E.,Jones, A.D.,Kaller, M.R.,Kunz, R.K.,Miller, S.,Monenschein, H.,Nguyen, T.,Pickrell, A.J.,Porter, A.,Reichelt, A.,Zhao, X.,Treanor, J.J.,Allen, J.R.
Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.
Bioorg.Med.Chem., 22:6570-6585, 2014

PubMed Abstract: We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.

PubMed: 25456383
DOI: 10.1016/j.bmc.2014.10.013

Experimental method

X-RAY DIFFRACTION (2.77 Å)