4FCB

Potent and Selective Phosphodiesterase 10A Inhibitors

4FCB の概要

• エントリーDOI: 10.2210/pdb4fcb/pdb
• 関連するPDBエントリー: 4FCD
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: binding sites, cyclic amp, cyclic gmp, ligands, phosphodiesterase inhibitors, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q9Y233
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80185.26

構造登録者

Parris, K.D. (登録日: 2012-05-24, 公開日: 2012-09-05, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)