4phw
From Proteopedia
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| - | ''' | + | ==Crystal Structure of PDE10A with 1H-benzimidazol-2-yl(4-((3-(tetrahydro-2H-pyran-4-yl)-2-pyridinyl)oxy)phenyl)methanone== |
| + | <StructureSection load='4phw' size='340' side='right' caption='[[4phw]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4phw]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PHW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PHW FirstGlance]. <br> | ||
| + | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2W1:1H-BENZIMIDAZOL-2-YL(4-{[3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRIDIN-2-YL]OXY}PHENYL)METHANONE'>2W1</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br> | ||
| + | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4phw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4phw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4phw RCSB], [http://www.ebi.ac.uk/pdbsum/4phw PDBsum]</span></td></tr> | ||
| + | <table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate. | ||
| - | + | Discovery of Clinical Candidate 1-(4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)e thanone (AMG 579), A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A).,Hu E, Chen N, Bourbeau MP, Harrington PE, Biswas K, Kunz RK, Andrews KL, Chmait S, Zhao X, Davis C, Ma J, Shi J, Lester-Zeiner D, Danao J, Able J, Cueva M, Talreja S, Kornecook T, Chen H, Porter A, Hungate R, Treanor J, Allen JR J Med Chem. 2014 Aug 4. PMID:25062128<ref>PMID:25062128</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Chmait, S.]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Keto-benzimidazole]] | ||
| + | [[Category: Phosphodiesterase]] | ||
Revision as of 02:29, 7 August 2014
Crystal Structure of PDE10A with 1H-benzimidazol-2-yl(4-((3-(tetrahydro-2H-pyran-4-yl)-2-pyridinyl)oxy)phenyl)methanone
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