April 8, 2013
These phosphodiesterase inhibitors may eventually treat neurological diseases. Inventors W. D. Schmitz, M. V. Debenedetto, and S. R. Kimura disclose compounds represented by formula 1 (Figure 1) that inhibit the enzyme phosphodiesterase 10 (PDE10). Figure 1 also shows the general synthesis of formula 1 compounds. (Boc is tert-butoxycarbonyl.)
PDEs are intracellular enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) to adenosine monophosphate, cyclic guanosine monophosphate (cGMP) to guanosine monophosphate, or both. The PDE10 enzyme hydrolyzes both cyclic phosphates. It is expressed in the brain, primarily in the medium spiny neurons (MSNs) of the striatum.
Inhibiting PDE10 is likely to increase the levels of cAMP and cGMP that serve as secondary messengers in several cellular pathways. Increasing cAMP and cGMP levels would enhance signaling intensity and affect key neural functions in the striatum.
PDE10 inhibitors such as molecules of formula 1 have the potential to treat psychiatric and neurological diseases. Some of the diseases mentioned by the inventors include schizophrenia; delusional disorder; substance-induced psychotic disorder; anxiety disorders; movement disorders such as Parkinson’s disease, Huntington’s disease, and restless-leg syndrome; and cognition deficiency disorders, such as Alzheimer’s disease and multi-infarct dementia.
The inventors prepared 30 compounds of formula 1. Compounds 2, 3, and 4 (Figure 2) are representative examples.
The inventors used the LE-PDE10A inhibition assay to assess the compounds. The IC50 data for the representative examples are shown in the table.
(Bristol-Myers Squibb [Princeton, NJ]. WIPO Publication 2013003298, Jan. 3, 2013; Ahmed F. Abdel-Magid)
This patent was originally reviewed in ACS Medicinal Chemistry Letters.