4PHW

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

Summary for 4PHW

• Entry DOI: 10.2210/pdb4phw/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: inhibitor, phosphodiesterase, keto-benzimidazole, 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: 82787.69

Authors

Chmait, S. (deposition date: 2014-05-07, release date: 2014-08-06, Last modification date: 2024-10-30)

Primary citation

Hu, E.,Chen, N.,Bourbeau, M.P.,Harrington, P.E.,Biswas, K.,Kunz, R.K.,Andrews, K.L.,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, J.R.
Discovery of Clinical Candidate 1-(4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A).
J.Med.Chem., 57:6632-6641, 2014

PubMed Abstract: 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.

PubMed: 25062128
DOI: 10.1021/jm500713j

Experimental method

X-RAY DIFFRACTION (2.5 Å)