Novel 2-methoxyacylhydrazones as potent, selective PDE10A inhibitors
with activity in animal models of schizophrenia
Neil S. Cutshall, Rene Onrust, Alex Rohde, Sasha Gragerov, Lauren Hamilton, Kevin Harbol, Hui-Rong Shen,
Shawn McKee, Charles Zuta, Galina Gragerova, Vince Florio, Thomas N. Wheeler, Jennifer L. Gage
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Omeros Corp., 1420 Fifth Ave, Suite 2600, Seattle, WA 98101, USA
article info
Article history:
Received 7 May 2012
Accepted 2 July 2012
Available online 10 July 2012
Keywords:
PDE10
PDE10A
Phosphodiesterase
Schizophrenia
Hydrazone
Hydrazide
PDE
Enzyme inhibitor
Cognitive
abstract
A series of 2-methoxyacylhydrazones were optimized to yield compounds with high affinity for PDE10A.
Several compounds demonstrated efficacy in animal models of schizophrenia, including conditioned
avoidance response and a pro-psychotic phencyclidine hyperactivity model.
Ó 2012 Elsevier Ltd. All rights reserved.
Schizophrenia is a debilitating disease affecting approximately
1% of the world population.
1
Current pharmaceutical agents used
to treat schizophrenia include the typical antipsychotics that effec-
tively address positive symptoms such as hallucinations and delu-
sions. These drugs exert their effect through action as D2 receptor
antagonists. However, some drawbacks of these medications are
motor side effects and lack of efficacy in a subset of the patient
population.
2
Contemporary ‘atypical’ antipsychotics possessing
mixed D2/5HT2A antagonism have reduced severity of motor side
effects, but can cause deleterious metabolic consequences. Besides
the need for new antipsychotic agents without unwanted side ef-
fects, pharmaceuticals are needed that address cognitive symp-
toms which include impairment of working memory and
executive function as well as negative symptoms such as social
withdrawal. The severity of the cognitive effects of schizophrenia
has been shown to be a predominant determinant in the overall
prognosis of patient function. Thus, pharmaceutical entities for
schizophrenia are needed that can manage both positive and neg-
ative symptoms along with cognitive deficits.
Phosphodiesterase 10A (PDE10A) is a dual-specificity phospho-
diesterase that hydrolyzes both cyclic adenosine and cyclic guano-
sine monophosphate (cAMP and cGMP).
3a
It is expressed
predominantly in brain, with highest concentrations in the med-
ium spiny neurons (MSNs) located in the striatum. Because of
the unique location of this enzyme, PDE10A inhibitors have been
studied for their potential as pharmaceutical agents for Parkinson’s
and Huntington’s disease, obsessive compulsive disorder, addiction
and schizophrenia.
3b
It has been shown that PDE10A inhibitors
have pharmacological effects in models of both the positive and
cognitive symptoms of schizophrenia. The molecular mechanisms
that lead to these in vivo effects continue to be elucidated and
these studies have been reviewed.
3b
One PDE10A inhibitor, MP-
10, was recently tested for the treatment of schizophrenia in Phase
2a clinical trials where it was found to lack efficacy in acute exac-
erbation of schizophrenia.
3b,c
It remains to be seen if PDE10 inhib-
itors will be effective in other indications.
We recently reported structure-activity relationship (SAR) stud-
ies on novel thioacetylhydrazones as potent inhibitors of PDE10A
with significant efficacy in animal models of schizophrenia.
4
A re-
lated series of compounds also containing the hydrazone function-
ality, but absent the thioether linker is described here. Thus, lead
compound racemic hydrazone 1 was discovered via a high-
throughput screening campaign (Fig. 1). Acylhydrazones have been
pursued as potential therapeutics for cancer (angiogenesis inhibi-
tors),
5a
inflammatory diseases (cysteine protease inhibitors),
5b
type 2 diabetes (glucagon receptor antagonists, taste receptor
modulators),
5c,d
dementia (calpain inhibitors),
5e
and HIV (reverse
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.007
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Corresponding author. Tel.: +1 206 676 0813; fax: +1 206 676 0808.
E-mail address: jgage@omeros.com (J.L. Gage).
Bioorganic & Medicinal Chemistry Letters 22 (2012) 5595–5599
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl