title: Synthesis and biological evaluation of novel 4-hydroxytamoxifen analogs as estrogen-related receptor gamma inverse agonists.
abstract: Estrogen-related receptor gamma (ERRγ) has recently been recognized as an attractive target for treating inflammation, cancer, and metabolic disorders. Herein, we discovered and demonstrated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that could act as highly selective inverse agonists for ERRγ. The results were comparable to those for GSK5182 (4), a leading ERRγ inverse agonist ligand. Briefly, the half-maximal inhibitory concentration (IC50) range of the synthesized compounds for ERRγ was 0.1-10 μM. Impressively, compound 24e exhibited potency comparable to 4 but was more selective for ERRγ over three other subtypes: ERRα, ERRβ, and estrogen receptor α. Furthermore, compound 24e exhibited a superior in vitro ADMET profile compared to the other compounds. Thus, the newly synthesized class of ERRγ inverse agonists could be lead candidates for developing clinical therapies for ERRγ-related disorders.
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Jina
authors.initials: J
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Jungwook
authors.initials: J
authors.lastname: Chin
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
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, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Yoo
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Seoyeon
authors.initials: S
authors.lastname: Woo
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Hee Jong
authors.initials: HJ
authors.lastname: Hwang
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Joong-Heui
authors.initials: JH
authors.lastname: Cho
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Seo
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Jaeyoung
authors.initials: J
authors.lastname: Song
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Hayoung
authors.initials: H
authors.lastname: Hwang
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Suk Kyoon
authors.initials: SK
authors.lastname: Yoon
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, 41404, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
authors.forename: Jae-Han
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
authors.forename: Seung-Yun
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
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, Republic of Korea.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, 41404, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea. Electronic address: rose1998@boryung.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, Republic of Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, 41404, Republic of Korea. Electronic address: sjcho@dgmif.re.kr.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Cho
mesh_terms: D054314:Drug Inverse Agonism; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C490917:ESRRG protein, human; D008024:Ligands; D011960:Receptors, Estrogen; D054852:Small Molecule Libraries; D013629:Tamoxifen; C016601:afimoxifene
keywords: ADMET; ERRγ inverse agonist; GSK5182; Nuclear receptor