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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chemistry Techniques, Synthetic
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Crystallography, X-Ray
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Disease Models, Animal
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Dizocilpine Maleate / pharmacology
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Drug Discovery
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Drug Evaluation, Preclinical / methods
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Humans
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Male
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacology*
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Phosphoric Diester Hydrolases / chemistry
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Phosphoric Diester Hydrolases / metabolism
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Pyrimidines / chemistry
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Rats, Wistar
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Schizophrenia / drug therapy
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Structure-Activity Relationship*
Substances
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Phosphodiesterase Inhibitors
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Pyrimidines
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Dizocilpine Maleate
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PDE10A protein, human
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Phosphoric Diester Hydrolases
Associated data
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PDB/5C1W
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PDB/5C28
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PDB/5C29
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PDB/5C2A
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PDB/5C2E
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PDB/5C2H