Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores

Autor:	Angela Berry, Edward Pack, Gerald Nabozny, Alison Kukulka, Kirrane Thomas M, Daniel Kuzmich, Raj Betageri, Jörg Bentzien, Richard M. Nelson, Carol A. Torcellini, Bachir Latli, Christian Harcken, Mark Panzenbeck, Tazmeen N. Fadra, Roger M. Dinallo, Ljiljana Zuvela-Jelaska, Gilmore Thomas A, Don Souza, Heewon Lee, Josephine Pelletier, Younes Bekkali, Dieter Wiedenmayer, John R. Regan, Susan E. Goldrick, David S. Thomson
Rok vydání:	2011
Předmět:	Agonist Models Molecular medicine.medical_specialty Indoles medicine.drug_class Clinical Biochemistry Pharmaceutical Science Pharmacology Biochemistry Transactivation Mice Structure-Activity Relationship Receptors Glucocorticoid Internal medicine Drug Discovery medicine Animals Humans Aromatase skin and connective tissue diseases Molecular Biology Glucocorticoids biology Chemistry Organic Chemistry In vitro Endocrinology biology.protein Prednisolone Molecular Medicine Pharmacophore Selectivity Glucocorticoid medicine.drug HeLa Cells
Zdroj:	Bioorganicmedicinal chemistry letters. 21(22)
ISSN:	1464-3405
Popis:	We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1a0894392651eead7a62f90ba3b953fd https://pubmed.ncbi.nlm.nih.gov/21963986 Zobrazit plný text záznamu Full Text from ScienceDirect