title: VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice.
abstract: Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation--NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone--but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases.
authors.affiliation: ReveraGen BioPharma, Rockville, Maryland, United States of America. Jesse.Damsker@reveragen.com
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Damsker
authors.forename: Blythe C
authors.initials: BC
authors.lastname: Dillingham
authors.forename: Mary C
authors.initials: MC
authors.lastname: Rose
authors.forename: Molly A
authors.initials: MA
authors.lastname: Balsley
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Heier
authors.forename: Alan M
authors.initials: AM
authors.lastname: Watson
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Stemmy
authors.forename: Roslyn A
authors.initials: RA
authors.lastname: Jurjus
authors.forename: Tony
authors.initials: T
authors.lastname: Huynh
authors.forename: Kathleen
authors.initials: K
authors.lastname: Tatem
authors.forename: Kitipong
authors.initials: K
authors.lastname: Uaesoontrachoon
authors.forename: Dana M
authors.initials: DM
authors.lastname: Berry
authors.forename: Angela S
authors.initials: AS
authors.lastname: Benton
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: John M
authors.initials: JM
authors.lastname: McCall
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Constant
authors.forename: Erica K M
authors.initials: EK
authors.lastname: Reeves
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000818:Animals; D001249:Asthma / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015550:Cell Degranulation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005938:Glucocorticoids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006967:Hypersensitivity / Q000150:complications* / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010047:Ovalbumin; D011014:Pneumonia / Q000150:complications* / Q000188:drug therapy*; D011244:Pregnadienediols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013977:Tibia / Q000187:drug effects / Q000473:pathology
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D016328:NF-kappa B; D011244:Pregnadienediols; C584811:VBP15 compound; D010047:Ovalbumin