4FCD

Potent and Selective Phosphodiesterase 10A Inhibitors

Summary for 4FCD

• Entry DOI: 10.2210/pdb4fcd/pdb
• Related: 4FCB
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: binding sites, cyclic amp, cyclic gmp, humans, hydrolysis, ligands, phosphodiesterase inhibitors, phosphoric diester hydrolases, recombinant proteins, structure-activity relationship, 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: 80101.87

Authors

Parris, K.D. (deposition date: 2012-05-24, release date: 2012-09-05, Last modification date: 2024-02-28)

Primary citation

Malamas, M.S.,Stange, H.,Schindler, R.,Lankau, H.J.,Grunwald, C.,Langen, B.,Egerland, U.,Hage, T.,Ni, Y.,Erdei, J.,Fan, K.Y.,Parris, K.,Marquis, K.L.,Grauer, S.,Brennan, J.,Navarra, R.,Graf, R.,Harrison, B.L.,Robichaud, A.,Kronbach, T.,Pangalos, M.N.,Brandon, N.J.,Hoefgen, N.
Novel triazines as potent and selective phosphodiesterase 10A inhibitors.
Bioorg.Med.Chem.Lett., 22:5876-5884, 2012

PubMed Abstract: The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2 mg/kg).

PubMed: 22902656
DOI: 10.1016/j.bmcl.2012.07.076

Experimental method

X-RAY DIFFRACTION (2.02 Å)