3HQW

Discovery of novel inhibitors of PDE10A

Summary for 3HQW

• Entry DOI: 10.2210/pdb3hqw/pdb
• Related: 3HQ1 3HQY 3HQZ
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase 10a pde10a pde inhibitors, allosteric enzyme, alternative splicing, camp, camp-binding, cgmp, cgmp-binding, cytoplasm, hydrolase, magnesium, metal-binding, nucleotide-binding, zinc, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Rattus norvegicus (rat)
• Cellular location: Cytoplasm : Q9QYJ6
• Total number of polymer chains: 1
• Total formula weight: 43771.75

Authors

Pandit, J.,Marr, E.S. (deposition date: 2009-06-08, release date: 2009-08-04, Last modification date: 2023-09-06)

Primary citation

Verhoest, P.R.,Chapin, D.S.,Corman, M.,Fonseca, K.,Harms, J.F.,Hou, X.,Marr, E.S.,Menniti, F.S.,Nelson, F.,O'Connor, R.,Pandit, J.,Proulx-Lafrance, C.,Schmidt, A.W.,Schmidt, C.J.,Suiciak, J.A.,Liras, S.
Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the Treatment of Schizophrenia
J.Med.Chem., 52:5188-5196, 2009

PubMed Abstract: By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.

PubMed: 19630403
DOI: 10.1021/jm900521k

Experimental method

X-RAY DIFFRACTION (1.7 Å)