3SNI

Highly Potent, Selective, and Orally Active Phosphodiestarase 10A Inhibitors

Summary for 3SNI

• Entry DOI: 10.2210/pdb3sni/pdb
• Related: 3SN7 3SNL
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: hydrolase, hydrolase inhibitor, zn binding, 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: 80101.91

Authors

Malamas, M.S.,Ni, Y.,Erdei, J.,Stange, H.,Schindler, R.,Lankau, H.-J.,Grunwald, C.,Fan, K.Y.,Parris, K.D.,Langen, B.,Egerland, U.,Hage, T.,Marquis, K.L.,Grauer, S.,Brennan, J.,Navarra, R.,Graf, R.,Harrison, B.L.,Robichaud, A.,Kronbach, T.,Pangalos, M.,Hofgen, N.,Brandon, N.J. (deposition date: 2011-06-29, release date: 2011-10-26, Last modification date: 2024-02-28)

Primary citation

Malamas, M.S.,Ni, Y.,Erdei, J.,Stange, H.,Schindler, R.,Lankau, H.J.,Grunwald, C.,Fan, K.Y.,Parris, K.,Langen, B.,Egerland, U.,Hage, T.,Marquis, K.L.,Grauer, S.,Brennan, J.,Navarra, R.,Graf, R.,Harrison, B.L.,Robichaud, A.,Kronbach, T.,Pangalos, M.N.,Hoefgen, N.,Brandon, N.J.
Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors.
J.Med.Chem., 54:7621-7638, 2011

PubMed Abstract: The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.

PubMed: 21988093
DOI: 10.1021/jm2009138

Experimental method

X-RAY DIFFRACTION (1.9 Å)