Dual 5-HT 2A and 5-HT 2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.

Autor:	Oguma T; Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Jino K; Laboratory for Drug Discovery & Disease Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Nakahara K; Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Asada H; Department of Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-yu, Kyoto 606-8501, Japan., Fuchino K; Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Nagatani K; Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Kouki K; Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Okamoto R; Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Takai N; Laboratory for Drug Discovery & Disease Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Koda K; Laboratory for Drug Discovery & Disease Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Fujita S; Laboratory for Drug Discovery & Disease Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Sekiguchi Y; Laboratory for Bio-Modality Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Yasuo K; Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Mayumi K; Laboratory for Drug Discovery & Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Abe A; Laboratory for Drug Discovery & Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Imono M; Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Horiguchi N; Laboratory for Drug Discovery & Disease Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Iwata S; Department of Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-yu, Kyoto 606-8501, Japan., Kusakabe KI; Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Aug 22; Vol. 67 (16), pp. 14478-14492. Date of Electronic Publication: 2024 Aug 13.
DOI:	10.1021/acs.jmedchem.4c01244
Abstrakt:	Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin ( 1 ), a 5-HT 2A receptor inverse agonist having minimal 5-HT 2C receptor affinity and no dopamine D 2 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-HT 2A and 5-HT 2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT 2A and 5-HT 2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT 2A and 5-HT 2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT 2C 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.
Databáze:	MEDLINE
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