Search

Your search keyword '"Nakahara, Kenji"' showing total 7 results
Start Over Author "Nakahara, Kenji" Journal journal of medicinal chemistry
7 results on '"Nakahara, Kenji"'

1. 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.

Author

Oguma, Takuya, Jino, Kohei, Nakahara, Kenji, Asada, Hidetsugu, Fuchino, Kouki, Nagatani, Kotaro, Kouki, Kensuke, Okamoto, Ryuji, Takai, Nozomi, Koda, Ken, Fujita, Sayaka, Sekiguchi, Yusuke, Yasuo, Kazuya, Mayumi, Kei, Abe, Ayane, Imono, Masaaki, Horiguchi, Naotaka, Iwata, So, and Kusakabe, Ken-ichi

Published
2024
Full Text
View/download PDF

2. Dual 5-HT2Aand 5-HT2CReceptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis

Author

Oguma, Takuya, Jino, Kohei, Nakahara, Kenji, Asada, Hidetsugu, Fuchino, Kouki, Nagatani, Kotaro, Kouki, Kensuke, Okamoto, Ryuji, Takai, Nozomi, Koda, Ken, Fujita, Sayaka, Sekiguchi, Yusuke, Yasuo, Kazuya, Mayumi, Kei, Abe, Ayane, Imono, Masaaki, Horiguchi, Naotaka, Iwata, So, and Kusakabe, Ken-ichi

Abstract

Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson’s disease psychosis, pimavanserin (1), a 5-HT2Areceptor inverse agonist having minimal 5-HT2Creceptor affinity and no dopamine D2receptor 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-HT2Aand 5-HT2Creceptor inverse agonist 8having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2Aand 5-HT2Creceptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2Aand 5-HT2Coccupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2Caffinity in 1followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8that showed significant antipsychotic efficacy due to the involvement of both receptors.

Published
2024
Full Text
View/download PDF

3. Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

Author

Unoh, Yuto, primary, Uehara, Shota, additional, Nakahara, Kenji, additional, Nobori, Haruaki, additional, Yamatsu, Yukiko, additional, Yamamoto, Shiho, additional, Maruyama, Yuki, additional, Taoda, Yoshiyuki, additional, Kasamatsu, Koji, additional, Suto, Takahiro, additional, Kouki, Kensuke, additional, Nakahashi, Atsufumi, additional, Kawashima, Sho, additional, Sanaki, Takao, additional, Toba, Shinsuke, additional, Uemura, Kentaro, additional, Mizutare, Tohru, additional, Ando, Shigeru, additional, Sasaki, Michihito, additional, Orba, Yasuko, additional, Sawa, Hirofumi, additional, Sato, Akihiko, additional, Sato, Takafumi, additional, Kato, Teruhisa, additional, and Tachibana, Yuki, additional

Published
2022
Full Text
View/download PDF

4. Discovery of an Extremely Potent Thiazine-Based β-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose

Author

Tadano, Genta, primary, Komano, Kazuo, additional, Yoshida, Shuhei, additional, Suzuki, Shinji, additional, Nakahara, Kenji, additional, Fuchino, Kouki, additional, Fujimoto, Kazuki, additional, Matsuoka, Eriko, additional, Yamamoto, Takahiko, additional, Asada, Naoya, additional, Ito, Hisanori, additional, Sakaguchi, Gaku, additional, Kanegawa, Naoki, additional, Kido, Yasuto, additional, Ando, Shigeru, additional, Fukushima, Tamio, additional, Teisman, Ard, additional, Urmaliya, Vijay, additional, Dhuyvetter, Deborah, additional, Borghys, Herman, additional, Van Den Bergh, An, additional, Austin, Nigel, additional, Gijsen, Harrie J. M., additional, Yamano, Yoshinori, additional, Iso, Yasuyoshi, additional, and Kusakabe, Ken-ichi, additional

Published
2019
Full Text
View/download PDF

5. Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2

Author

Fujimoto, Kazuki, primary, Matsuoka, Eriko, additional, Asada, Naoya, additional, Tadano, Genta, additional, Yamamoto, Takahiko, additional, Nakahara, Kenji, additional, Fuchino, Kouki, additional, Ito, Hisanori, additional, Kanegawa, Naoki, additional, Moechars, Diederik, additional, Gijsen, Harrie J. M., additional, and Kusakabe, Ken-ichi, additional

Published
2019
Full Text
View/download PDF

6. Discovery of Potent and Centrally Active 6-Substituted 5-Fluoro-1,3-dihydro-oxazine β-Secretase (BACE1) Inhibitors via Active Conformation Stabilization

Author

Nakahara, Kenji, primary, Fuchino, Kouki, additional, Komano, Kazuo, additional, Asada, Naoya, additional, Tadano, Genta, additional, Hasegawa, Tsuyoshi, additional, Yamamoto, Takahiko, additional, Sako, Yusuke, additional, Ogawa, Masayoshi, additional, Unemura, Chie, additional, Hosono, Motoko, additional, Ito, Hisanori, additional, Sakaguchi, Gaku, additional, Ando, Shigeru, additional, Ohnishi, Shuichi, additional, Kido, Yasuto, additional, Fukushima, Tamio, additional, Dhuyvetter, Deborah, additional, Borghys, Herman, additional, Gijsen, Harrie J. M., additional, Yamano, Yoshinori, additional, Iso, Yasuyoshi, additional, and Kusakabe, Ken-ichi, additional

Published
2018
Full Text
View/download PDF

7. 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.

Author

Oguma T, Jino K, Nakahara K, Asada H, Fuchino K, Nagatani K, Kouki K, Okamoto R, Takai N, Koda K, Fujita S, Sekiguchi Y, Yasuo K, Mayumi K, Abe A, Imono M, Horiguchi N, Iwata S, and Kusakabe KI

Subjects
Animals, Humans, Structure-Activity Relationship, Male, Drug Inverse Agonism, ERG1 Potassium Channel metabolism, ERG1 Potassium Channel antagonists & inhibitors, Rats, Mice, Piperidines pharmacology, Piperidines therapeutic use, Piperidines chemistry, Rats, Sprague-Dawley, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ether-A-Go-Go Potassium Channels metabolism, Urea analogs & derivatives, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Antipsychotic Agents chemistry, Antipsychotic Agents chemical synthesis, Receptor, Serotonin, 5-HT2A metabolism, Psychotic Disorders drug therapy, Serotonin 5-HT2 Receptor Agonists pharmacology, Serotonin 5-HT2 Receptor Agonists therapeutic use, Serotonin 5-HT2 Receptor Agonists chemistry, Receptor, Serotonin, 5-HT2C metabolism, Dementia drug therapy
Abstract

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.

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results