Property based optimization of δ-lactam HDAC inhibitors for metabolic stability

Hong Chul Yoon; Eunhyun Choi; Jung Eun Park; Misun Cho; Jeong Jea Seo; Soo Jin Oh; Jong Soon Kang; Hwan Mook Kim; Song Kyu Park; Kiho Lee; Gyoonhee Han

doi:10.1016/j.bmcl.2010.08.117

Property based optimization of δ-lactam HDAC inhibitors for metabolic stability

Hong Chul Yoon, Eunhyun Choi, Jung Eun Park, Misun Cho, Jeong Jea Seo, Soo Jin Oh, Jong Soon Kang, Hwan Mook Kim, Song Kyu Park, Kiho Lee, Gyoonhee Han

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

Abstract

The novel δ-lactam based HDAC inhibitor, KBH-A118 (3) shows a good HDAC enzyme and cancer cell growth inhibitory activities but has undesirable pharmacokinetics profiles because of instability in mouse liver microsome. To improve metabolic stability, various analogues were prepared with substituents on aromatic ring of cap group and various chain lengths between the cap group and δ-lactam core. The newly prepared analogues showed moderate to potent in vitro activities. Among them six compounds (8a, 8e, 8j, 8n, 8t, and 8v) were evaluated on mouse liver microsome assay and it turned out that the microsomal stabilities were dependent on lipophilicity and the number of the rotatable bonds. Finally, the animal pharmacokinetic profiles of 8e displayed improving oral exposure and oral bioavailability.

Original language	English
Pages (from-to)	6808-6811
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	22
DOIs	https://doi.org/10.1016/j.bmcl.2010.08.117
Publication status	Published - 2010 Nov 15

Bibliographical note

Funding Information:
This research was supported by National Research Foundation ( 2009-0092966 ), Korea Research WCU grant ( R31-2008-000-10086-0 ) and Brain Korea 21 project, Republic of Korea.

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2010.08.117

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title = "Property based optimization of δ-lactam HDAC inhibitors for metabolic stability",

abstract = "The novel δ-lactam based HDAC inhibitor, KBH-A118 (3) shows a good HDAC enzyme and cancer cell growth inhibitory activities but has undesirable pharmacokinetics profiles because of instability in mouse liver microsome. To improve metabolic stability, various analogues were prepared with substituents on aromatic ring of cap group and various chain lengths between the cap group and δ-lactam core. The newly prepared analogues showed moderate to potent in vitro activities. Among them six compounds (8a, 8e, 8j, 8n, 8t, and 8v) were evaluated on mouse liver microsome assay and it turned out that the microsomal stabilities were dependent on lipophilicity and the number of the rotatable bonds. Finally, the animal pharmacokinetic profiles of 8e displayed improving oral exposure and oral bioavailability.",

author = "Yoon, {Hong Chul} and Eunhyun Choi and Park, {Jung Eun} and Misun Cho and Seo, {Jeong Jea} and Oh, {Soo Jin} and Kang, {Jong Soon} and Kim, {Hwan Mook} and Park, {Song Kyu} and Kiho Lee and Gyoonhee Han",

note = "Funding Information: This research was supported by National Research Foundation ( 2009-0092966 ), Korea Research WCU grant ( R31-2008-000-10086-0 ) and Brain Korea 21 project, Republic of Korea. ",

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doi = "10.1016/j.bmcl.2010.08.117",

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AU - Yoon, Hong Chul

AU - Choi, Eunhyun

AU - Park, Jung Eun

AU - Cho, Misun

AU - Seo, Jeong Jea

AU - Oh, Soo Jin

AU - Kang, Jong Soon

AU - Kim, Hwan Mook

AU - Park, Song Kyu

AU - Lee, Kiho

AU - Han, Gyoonhee

N1 - Funding Information: This research was supported by National Research Foundation ( 2009-0092966 ), Korea Research WCU grant ( R31-2008-000-10086-0 ) and Brain Korea 21 project, Republic of Korea.

PY - 2010/11/15

Y1 - 2010/11/15

N2 - The novel δ-lactam based HDAC inhibitor, KBH-A118 (3) shows a good HDAC enzyme and cancer cell growth inhibitory activities but has undesirable pharmacokinetics profiles because of instability in mouse liver microsome. To improve metabolic stability, various analogues were prepared with substituents on aromatic ring of cap group and various chain lengths between the cap group and δ-lactam core. The newly prepared analogues showed moderate to potent in vitro activities. Among them six compounds (8a, 8e, 8j, 8n, 8t, and 8v) were evaluated on mouse liver microsome assay and it turned out that the microsomal stabilities were dependent on lipophilicity and the number of the rotatable bonds. Finally, the animal pharmacokinetic profiles of 8e displayed improving oral exposure and oral bioavailability.

AB - The novel δ-lactam based HDAC inhibitor, KBH-A118 (3) shows a good HDAC enzyme and cancer cell growth inhibitory activities but has undesirable pharmacokinetics profiles because of instability in mouse liver microsome. To improve metabolic stability, various analogues were prepared with substituents on aromatic ring of cap group and various chain lengths between the cap group and δ-lactam core. The newly prepared analogues showed moderate to potent in vitro activities. Among them six compounds (8a, 8e, 8j, 8n, 8t, and 8v) were evaluated on mouse liver microsome assay and it turned out that the microsomal stabilities were dependent on lipophilicity and the number of the rotatable bonds. Finally, the animal pharmacokinetic profiles of 8e displayed improving oral exposure and oral bioavailability.

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Property based optimization of δ-lactam HDAC inhibitors for metabolic stability

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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