Discovery of Benzylpiperazine Derivatives as CNS-Penetrant and Selective Histone Deacetylase 6 Inhibitors
Inhibition of histone deacetylase 6 (HDAC6) in the brain is a highly attractive therapeutic target for the treatment of neurodegenerative diseases. The low blood–brain barrier permeability of most known HDAC6 inhibitors, however, prevents their application as central nervous system (CNS) drugs. To o...
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| Published in | ACS medicinal chemistry letters Vol. 13; no. 7; pp. 1077 - 1082 |
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| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
14.07.2022
Amer Chemical Soc |
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| Abstract | Inhibition of histone deacetylase 6 (HDAC6) in the brain is a highly attractive therapeutic target for the treatment of neurodegenerative diseases. The low blood–brain barrier permeability of most known HDAC6 inhibitors, however, prevents their application as central nervous system (CNS) drugs. To overcome this problem, we designed and synthesized benzylpiperazine derivatives using a hybrid strategy of combining HDAC6 inhibitors and brain-penetrant histamine H1 receptor antagonists. Introducing the benzylpiperazine units to the cap region of hydroxamate-type HDAC6 inhibitors led us to identify isozyme-selective and CNS-penetrant HDAC6 inhibitor KH-259 (1) with the appropriate pharmacokinetic and safety properties. Intraperitoneal administration of KH-259 (10 mg/kg) had antidepressant activity and increased acetylated α-tubulin in the brain without promoting acetylated histone H3K9. These findings indicate that our hybrid strategy of combining HDAC6 inhibitors and histamine H1 receptor antagonists is an effective methodology for designing CNS-penetrant HDAC6 inhibitors. |
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| AbstractList | Inhibition of histone deacetylase 6 (HDAC6) in the brain is a highly attractive therapeutic target for the treatment of neurodegenerative diseases. The low blood-brain barrier permeability of most known HDAC6 inhibitors, however, prevents their application as central nervous system (CNS) drugs. To overcome this problem, we designed and synthesized benzylpiperazine derivatives using a hybrid strategy of combining HDAC6 inhibitors and brain-penetrant histamine H
receptor antagonists. Introducing the benzylpiperazine units to the cap region of hydroxamate-type HDAC6 inhibitors led us to identify isozyme-selective and CNS-penetrant HDAC6 inhibitor KH-259 (
) with the appropriate pharmacokinetic and safety properties. Intraperitoneal administration of KH-259 (10 mg/kg) had antidepressant activity and increased acetylated α-tubulin in the brain without promoting acetylated histone H3K9. These findings indicate that our hybrid strategy of combining HDAC6 inhibitors and histamine H
receptor antagonists is an effective methodology for designing CNS-penetrant HDAC6 inhibitors. Inhibition of histone deacetylase 6 (HDAC6) in the brain is a highly attractive therapeutic target for the treatment of neurodegenerative diseases. The low blood-brain barrier permeability of most known HDAC6 inhibitors, however, prevents their application as central nervous system (CNS) drugs. To overcome this problem, we designed and synthesized benzylpiperazine derivatives using a hybrid strategy of combining HDAC6 inhibitors and brain-penetrant histamine H-1 receptor antagonists. Introducing the benzylpiperazine units to the cap region of hydroxamate-type HDAC6 inhibitors led us to identify isozyme-selective and CNS-penetrant HDAC6 inhibitor KH-259 (1) with the appropriate pharmacokinetic and safety properties. Intraperitoneal administration of KH-259 (10 mg/kg) had antidepressant activity and increased acetylated alpha-tubulin in the brain without promoting acetylated histone H3K9. These findings indicate that our hybrid strategy of combining HDAC6 inhibitors and histamine H-1 receptor antagonists is an effective methodology for designing CNS-penetrant HDAC6 inhibitors. Inhibition of histone deacetylase 6 (HDAC6) in the brain is a highly attractive therapeutic target for the treatment of neurodegenerative diseases. The low blood–brain barrier permeability of most known HDAC6 inhibitors, however, prevents their application as central nervous system (CNS) drugs. To overcome this problem, we designed and synthesized benzylpiperazine derivatives using a hybrid strategy of combining HDAC6 inhibitors and brain-penetrant histamine H1 receptor antagonists. Introducing the benzylpiperazine units to the cap region of hydroxamate-type HDAC6 inhibitors led us to identify isozyme-selective and CNS-penetrant HDAC6 inhibitor KH-259 (1) with the appropriate pharmacokinetic and safety properties. Intraperitoneal administration of KH-259 (10 mg/kg) had antidepressant activity and increased acetylated α-tubulin in the brain without promoting acetylated histone H3K9. These findings indicate that our hybrid strategy of combining HDAC6 inhibitors and histamine H1 receptor antagonists is an effective methodology for designing CNS-penetrant HDAC6 inhibitors. Inhibition of histone deacetylase 6 (HDAC6) in the brain is a highly attractive therapeutic target for the treatment of neurodegenerative diseases. The low blood–brain barrier permeability of most known HDAC6 inhibitors, however, prevents their application as central nervous system (CNS) drugs. To overcome this problem, we designed and synthesized benzylpiperazine derivatives using a hybrid strategy of combining HDAC6 inhibitors and brain-penetrant histamine H 1 receptor antagonists. Introducing the benzylpiperazine units to the cap region of hydroxamate-type HDAC6 inhibitors led us to identify isozyme-selective and CNS-penetrant HDAC6 inhibitor KH-259 ( 1 ) with the appropriate pharmacokinetic and safety properties. Intraperitoneal administration of KH-259 (10 mg/kg) had antidepressant activity and increased acetylated α-tubulin in the brain without promoting acetylated histone H3K9. These findings indicate that our hybrid strategy of combining HDAC6 inhibitors and histamine H 1 receptor antagonists is an effective methodology for designing CNS-penetrant HDAC6 inhibitors. |
| Author | Sumiyoshi, Takaaki Nagaoka, Yasuo Ito, Akihiro Lin, Bangzhong Ito, Takashi K. Yoshida, Minoru Hashimoto, Kosuke Arata, Mayumi Nakata, Akiko Kudo, Norio Nunomura, Kazuto Tsuganezawa, Keiko Ide, Soichiro |
| AuthorAffiliation | Seed Compounds Exploratory Unit for Drug Discovery Platform Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science Department of Biotechnology The University of Tokyo Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering Addictive Substance Project Drug Discovery Structural Biology Platform Unit School of Life Sciences |
| AuthorAffiliation_xml | – name: The University of Tokyo – name: Department of Biotechnology – name: Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science – name: Addictive Substance Project – name: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering – name: Drug Discovery Structural Biology Platform Unit – name: School of Life Sciences – name: Seed Compounds Exploratory Unit for Drug Discovery Platform |
| Author_xml | – sequence: 1 givenname: Kosuke surname: Hashimoto fullname: Hashimoto, Kosuke organization: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering – sequence: 2 givenname: Soichiro surname: Ide fullname: Ide, Soichiro organization: Addictive Substance Project – sequence: 3 givenname: Mayumi surname: Arata fullname: Arata, Mayumi organization: Seed Compounds Exploratory Unit for Drug Discovery Platform – sequence: 4 givenname: Akiko surname: Nakata fullname: Nakata, Akiko organization: Seed Compounds Exploratory Unit for Drug Discovery Platform – sequence: 5 givenname: Akihiro surname: Ito fullname: Ito, Akihiro organization: School of Life Sciences – sequence: 6 givenname: Takashi K. surname: Ito fullname: Ito, Takashi K. organization: Seed Compounds Exploratory Unit for Drug Discovery Platform – sequence: 7 givenname: Norio surname: Kudo fullname: Kudo, Norio organization: Seed Compounds Exploratory Unit for Drug Discovery Platform – sequence: 8 givenname: Bangzhong surname: Lin fullname: Lin, Bangzhong organization: Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science – sequence: 9 givenname: Kazuto surname: Nunomura fullname: Nunomura, Kazuto organization: Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science – sequence: 10 givenname: Keiko surname: Tsuganezawa fullname: Tsuganezawa, Keiko organization: Drug Discovery Structural Biology Platform Unit – sequence: 11 givenname: Minoru surname: Yoshida fullname: Yoshida, Minoru organization: The University of Tokyo – sequence: 12 givenname: Yasuo surname: Nagaoka fullname: Nagaoka, Yasuo organization: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering – sequence: 13 givenname: Takaaki orcidid: 0000-0002-2073-4365 surname: Sumiyoshi fullname: Sumiyoshi, Takaaki email: t-sumiyo@kansai-u.ac.jp organization: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35859864$$D View this record in MEDLINE/PubMed |
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| Keywords | selective inhibitor HDAC6 phenylhydroxamate brain penetration antidepressant DESIGN ACETYLATION TAU AXONAL-TRANSPORT MOUSE MODEL IN-VIVO DISEASE HDAC6 INHIBITORS STRESS COGNITIVE DEFICITS |
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| Title | Discovery of Benzylpiperazine Derivatives as CNS-Penetrant and Selective Histone Deacetylase 6 Inhibitors |
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