5C29

PDE10 complexed with 6-chloro-2-cyclopropyl-5-methyl-N-propyl-pyrimidin-4-amine

Summary for 5C29

• Entry DOI: 10.2210/pdb5c29/pdb
• Related: 5C1W 5C28 5C2A 5C2E 5C2H
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase, inhibitor, complex, 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: 83396.15

Authors

Yan, Y. (deposition date: 2015-06-15, release date: 2015-09-30, Last modification date: 2024-10-16)

Primary citation

Shipe, W.D.,Sharik, S.S.,Barrow, J.C.,McGaughey, G.B.,Theberge, C.R.,Uslaner, J.M.,Yan, Y.,Renger, J.J.,Smith, S.M.,Coleman, P.J.,Cox, C.D.
Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.
J.Med.Chem., 58:7888-7894, 2015

PubMed Abstract: Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.

PubMed: 26378882
DOI: 10.1021/acs.jmedchem.5b00983

Experimental method

X-RAY DIFFRACTION (2.05 Å)