title: 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.
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. jina@dgmif.re.kr.
authors.forename: Jina
authors.initials: J
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. cyim@dgmif.re.kr.
authors.forename: Chun Young
authors.initials: CY
authors.lastname: Im
authors.affiliation: Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Korea. tong-e@hanmail.net.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Yoo
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. minjung@dgmif.re.kr.
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Ma
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. ksb2014@dgmif.re.kr.
authors.forename: Sang-Bum
authors.initials: SB
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. turtulee@dgmif.re.kr.
authors.forename: Eunmi
authors.initials: E
authors.lastname: Hong
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. jwchin@dgmif.re.kr.
authors.forename: Jungwook
authors.initials: J
authors.lastname: Chin
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. hwanghy@dgmif.re.kr.
authors.forename: Hayoung
authors.initials: H
authors.lastname: Hwang
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. swlee@dgmif.re.kr.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. namdoo@dgmif.re.kr.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Korea. ggoloo@hanmail.net.|Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea. ggoloo@hanmail.net.
authors.forename: Jae-Han
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Korea. leei@knu.ac.kr.|Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea. leei@knu.ac.kr.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea. jeon9014@gmail.com.
authors.forename: Yong Hyun
authors.initials: YH
authors.lastname: Jeon
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Korea. hsc@chonnam.ac.kr.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. seongheonk15@yuhan.co.kr.
authors.forename: Seong Heon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea. sjcho@dgmif.re.kr.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Cho
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004355:Drug Stability; D000072237:ERG1 Potassium Channel; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004967:Estrogens / Q000138:chemical synthesis / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D051381:Rats; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D000072237:ERG1 Potassium Channel; C490917:ESRRG protein, human; D004967:Estrogens; D051638:Ether-A-Go-Go Potassium Channels; C583041:GSK5182; D008024:Ligands; D011960:Receptors, Estrogen; D054852:Small Molecule Libraries; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System
keywords: ADMET; GSK5182; estrogen-related receptor gamma; inverse agonist