4DDL

PDE10a Crystal Structure Complexed with Novel Inhibitor

Summary for 4DDL

• Entry DOI: 10.2210/pdb4ddl/pdb
• Related: 2OUP
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase 10a, hydrolase, 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: 80326.79

Authors

Chmait, S.,Jordan, S.,Zhang, J. (deposition date: 2012-01-18, release date: 2012-03-21)

Primary citation

Hu, E.,Kunz, R.K.,Rumfelt, S.,Chen, N.,Burli, R.,Li, C.,Andrews, K.L.,Zhang, J.,Chmait, S.,Kogan, J.,Lindstrom, M.,Hitchcock, S.A.,Treanor, J.
Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors.
Bioorg.Med.Chem.Lett., 22:2262-2265, 2012

PubMed Abstract: We report the discovery of 6,7-dimethoxy-4-(pyridin-3-yl)cinnolines as novel inhibitors of phosphodiesterase 10A (PDE10A). Systematic examination and analyses of structure-activity-relationships resulted in single digit nM potency against PDE10A. X-ray co-crystal structure revealed the mode of binding in the enzyme's catalytic domain and the source of selectivity against other PDEs. High in vivo clearance in rats was addressed with the help of metabolite identification (ID) studies. These findings combined resulted in compound 39, a promising potent inhibitor of PDE10A with good in vivo metabolic stability in rats and efficacy in a rodent behavioral model.

PubMed: 22365755
DOI: 10.1016/j.bmcl.2012.01.086

Experimental method

X-RAY DIFFRACTION (2.07 Å)