Identification of Selective ERRγ Inverse Agonists

GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds...
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Autor*in:	Jina Kim [verfasserIn] Chun Young Im [verfasserIn] Eun Kyung Yoo [verfasserIn] Min Jung Ma [verfasserIn] Sang-Bum Kim [verfasserIn] Eunmi Hong [verfasserIn] Jungwook Chin [verfasserIn] Hayoung Hwang [verfasserIn] Sungwoo Lee [verfasserIn] Nam Doo Kim [verfasserIn] Jae-Han Jeon [verfasserIn] In-Kyu Lee [verfasserIn] Yong Hyun Jeon [verfasserIn] Hueng-Sik Choi [verfasserIn] Seong Heon Kim [verfasserIn] Sung Jin Cho [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2016

Schlagwörter:	estrogen-related receptor gamma inverse agonist ADMET GSK5182

Übergeordnetes Werk:	In: Molecules - MDPI AG, 2003, 21(2016), 1, p 80
Übergeordnetes Werk:	volume:21 ; year:2016 ; number:1, p 80

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/molecules21010080

Katalog-ID:	DOAJ011644931

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spelling	10.3390/molecules21010080 doi (DE-627)DOAJ011644931 (DE-599)DOAJ51d474224d844cfc9eb9d3b1036ceb23 DE-627 ger DE-627 rakwb eng QD241-441 Jina Kim verfasserin aut Identification of Selective ERRγ Inverse Agonists 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases. estrogen-related receptor gamma inverse agonist ADMET GSK5182 Organic chemistry Chun Young Im verfasserin aut Eun Kyung Yoo verfasserin aut Min Jung Ma verfasserin aut Sang-Bum Kim verfasserin aut Eunmi Hong verfasserin aut Jungwook Chin verfasserin aut Hayoung Hwang verfasserin aut Sungwoo Lee verfasserin aut Nam Doo Kim verfasserin aut Jae-Han Jeon verfasserin aut In-Kyu Lee verfasserin aut Yong Hyun Jeon verfasserin aut Hueng-Sik Choi verfasserin aut Seong Heon Kim verfasserin aut Sung Jin Cho verfasserin aut In Molecules MDPI AG, 2003 21(2016), 1, p 80 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:21 year:2016 number:1, p 80 https://doi.org/10.3390/molecules21010080 kostenfrei https://doaj.org/article/51d474224d844cfc9eb9d3b1036ceb23 kostenfrei http://www.mdpi.com/1420-3049/21/1/80 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2016 1, p 80
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allfieldsSound	10.3390/molecules21010080 doi (DE-627)DOAJ011644931 (DE-599)DOAJ51d474224d844cfc9eb9d3b1036ceb23 DE-627 ger DE-627 rakwb eng QD241-441 Jina Kim verfasserin aut Identification of Selective ERRγ Inverse Agonists 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases. estrogen-related receptor gamma inverse agonist ADMET GSK5182 Organic chemistry Chun Young Im verfasserin aut Eun Kyung Yoo verfasserin aut Min Jung Ma verfasserin aut Sang-Bum Kim verfasserin aut Eunmi Hong verfasserin aut Jungwook Chin verfasserin aut Hayoung Hwang verfasserin aut Sungwoo Lee verfasserin aut Nam Doo Kim verfasserin aut Jae-Han Jeon verfasserin aut In-Kyu Lee verfasserin aut Yong Hyun Jeon verfasserin aut Hueng-Sik Choi verfasserin aut Seong Heon Kim verfasserin aut Sung Jin Cho verfasserin aut In Molecules MDPI AG, 2003 21(2016), 1, p 80 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:21 year:2016 number:1, p 80 https://doi.org/10.3390/molecules21010080 kostenfrei https://doaj.org/article/51d474224d844cfc9eb9d3b1036ceb23 kostenfrei http://www.mdpi.com/1420-3049/21/1/80 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2016 1, p 80
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authorswithroles_txt_mv	Jina Kim @@aut@@ Chun Young Im @@aut@@ Eun Kyung Yoo @@aut@@ Min Jung Ma @@aut@@ Sang-Bum Kim @@aut@@ Eunmi Hong @@aut@@ Jungwook Chin @@aut@@ Hayoung Hwang @@aut@@ Sungwoo Lee @@aut@@ Nam Doo Kim @@aut@@ Jae-Han Jeon @@aut@@ In-Kyu Lee @@aut@@ Yong Hyun Jeon @@aut@@ Hueng-Sik Choi @@aut@@ Seong Heon Kim @@aut@@ Sung Jin Cho @@aut@@
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callnumber-first	Q - Science
author	Jina Kim
spellingShingle	Jina Kim misc QD241-441 misc estrogen-related receptor gamma misc inverse agonist misc ADMET misc GSK5182 misc Organic chemistry Identification of Selective ERRγ Inverse Agonists
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topic_title	QD241-441 Identification of Selective ERRγ Inverse Agonists estrogen-related receptor gamma inverse agonist ADMET GSK5182
topic	misc QD241-441 misc estrogen-related receptor gamma misc inverse agonist misc ADMET misc GSK5182 misc Organic chemistry
topic_unstemmed	misc QD241-441 misc estrogen-related receptor gamma misc inverse agonist misc ADMET misc GSK5182 misc Organic chemistry
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title	Identification of Selective ERRγ Inverse Agonists
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title_full	Identification of Selective ERRγ Inverse Agonists
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author_browse	Jina Kim Chun Young Im Eun Kyung Yoo Min Jung Ma Sang-Bum Kim Eunmi Hong Jungwook Chin Hayoung Hwang Sungwoo Lee Nam Doo Kim Jae-Han Jeon In-Kyu Lee Yong Hyun Jeon Hueng-Sik Choi Seong Heon Kim Sung Jin Cho
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title_sort	identification of selective errγ inverse agonists
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title_auth	Identification of Selective ERRγ Inverse Agonists
abstract	GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.
abstractGer	GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.
abstract_unstemmed	GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.
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container_issue	1, p 80
title_short	Identification of Selective ERRγ Inverse Agonists
url	https://doi.org/10.3390/molecules21010080 https://doaj.org/article/51d474224d844cfc9eb9d3b1036ceb23 http://www.mdpi.com/1420-3049/21/1/80 https://doaj.org/toc/1420-3049
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author2	Chun Young Im Eun Kyung Yoo Min Jung Ma Sang-Bum Kim Eunmi Hong Jungwook Chin Hayoung Hwang Sungwoo Lee Nam Doo Kim Jae-Han Jeon In-Kyu Lee Yong Hyun Jeon Hueng-Sik Choi Seong Heon Kim Sung Jin Cho
author2Str	Chun Young Im Eun Kyung Yoo Min Jung Ma Sang-Bum Kim Eunmi Hong Jungwook Chin Hayoung Hwang Sungwoo Lee Nam Doo Kim Jae-Han Jeon In-Kyu Lee Yong Hyun Jeon Hueng-Sik Choi Seong Heon Kim Sung Jin Cho
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doi_str	10.3390/molecules21010080
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up_date	2024-07-03T21:27:05.512Z
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Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, &gt;10, &gt;10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. 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Identification of Selective ERRγ Inverse Agonists

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