title: Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore.
abstract: Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA. Electronic address: hossein.razavi@boehringer-ingelheim.com.
authors.forename: Hossein
authors.initials: H
authors.lastname: Razavi
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Doris
authors.initials: D
authors.lastname: Riether
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Harcken
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bentzien
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Dinallo
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Souza
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Nelson
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Kukulka
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Tazmeen N
authors.initials: TN
authors.lastname: Fadra-Khan
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pack
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Zuvela-Jelaska
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Panzenbeck
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Torcellini
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Proudfoot
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Nabozny
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Thomson
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001168:Arthritis / Q000188:drug therapy; D001665:Binding Sites; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005938:Glucocorticoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D000432:Methanol / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011239:Prednisolone / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists*
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D011239:Prednisolone; D000432:Methanol
keywords: Agonist; Dissociated; Glucocorticoids; Non-steroidal; Nuclear hormone receptors