2. Academic Validation
  3. Dual 5-HT2A and 5-HT2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis

Dual 5-HT2A and 5-HT2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis

  • J Med Chem. 2024 Aug 22;67(16):14478-14492. doi: 10.1021/acs.jmedchem.4c01244.
Takuya Oguma 1,  Kohei Jino 2,  Kenji Nakahara 1,  Hidetsugu Asada 3,  Kouki Fuchino 1,  Kotaro Nagatani 1,  Kensuke Kouki 1,  Ryuji Okamoto 1,  Nozomi Takai 2,  Ken Koda 2,  Sayaka Fujita 2,  Yusuke Sekiguchi 4,  Kazuya Yasuo 1,  Kei Mayumi 5,  Ayane Abe 5,  Masaaki Imono 1,  Naotaka Horiguchi 2,  So Iwata 3,  Ken-Ichi Kusakabe 1
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 2 Laboratory for Drug Discovery & Disease Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 3 Department of Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-yu, Kyoto 606-8501, Japan.
  • 4 Laboratory for Bio-Modality Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 5 Laboratory for Drug Discovery & Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
PMID: 39137033 DOI: 10.1021/acs.jmedchem.4c01244
Abstract

Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (1), a 5-HT2A receptor inverse agonist having minimal 5-HT2C receptor affinity and no dopamine D2 receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2A and 5-HT2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2A and 5-HT2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2A and 5-HT2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.

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