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IMS-P21 Discovery of ASP5736, a Novel 5-HT5A Receptor Antagonist as an Antipsychotic Drug
Takuya WASHIO1, Osamu KANEKO1, Yuichiro KAWAMOTO1, Mayako YAMAZAKI1,
Masahiro FUJII1, Toshihiro WATANABE1
Discovery Research, Astellas Pharma Inc., 2Development, Astellas Pharma Inc.
The 5-HT5A receptor is a G-protein-coupled seven-transmembrane receptor and expresses predominantly in
neural tissues such as hippocampus, thalamus, amygdala and cerebral cortex with little expression in peripheral
tissues. 5-HT5A KO mice were reported to show increased exploratory activity in response to novel environments.
These observations suggested that the 5-HT5A receptor is involved in regulation of mood, affective disorder, and
cognitive function. Therefore, the 5-HT5A receptor is considered as a potential clinical target for the treatment of
As part of our research program directed at the development of new 5-HT5A receptor antagonists, we have
identified ASP5736 as a clinical candidate. ASP5736 is a potent and selective 5-HT5A receptor antagonist, and
showed promising preclinical pharmacological profiles in several animal models of schizophrenia without
specific toxicities such as sedation, catalepsy, or increase in plasma prolactin. In this presentation, we will show
the synthesis, SAR of this novel series of 5-HT5A receptor antagonists, and pharmacological profiles of ASP5736.