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
  • 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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