4phw

From Proteopedia

Crystal Structure of PDE10A with 1H-benzimidazol-2-yl(4-((3-(tetrahydro-2H-pyran-4-yl)-2-pyridinyl)oxy)phenyl)methanone

PDB ID 4phw

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Structural highlights

4phw is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PDE10_HUMAN Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7. Epub 2007 Mar 26. PMID:17389385
↑ 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. 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). J Med Chem. 2014 Aug 4. PMID:25062128 doi:http://dx.doi.org/10.1021/jm500713j