Characterization of ZK 245186, a novel, selective glucocorticoid receptor agonist for the topical treatment of inflammatory skin diseases.
OBJECTIVE
Glucocorticoids are highly effective in the therapy of inflammatory diseases. Their value, however, is limited by side effects. The discovery of the molecular mechanisms of the glucocorticoid receptor and the recognition that activation and repression of gene expression could be addressed separately opened the possibility of achieving improved safety profiles by the identification of ligands that predominantly induce repression. Here we report on ZK 245186, a novel, non-steroidal, low-molecular-weight, glucocorticoid receptor-selective agonist for the topical treatment of inflammatory dermatoses.


METHODS
Pharmacological properties of ZK 245186 and reference compounds were studied in terms of their potential anti-inflammatory and side effects in functional bioassays in vitro and in rodent models in vivo.


RESULTS
Anti-inflammatory activity of ZK 245186 was demonstrated in in vitro assays for inhibition of cytokine secretion and T cell proliferation. In vivo, using irritant contact dermatitis and T cell-mediated contact allergy models in mice and rats, ZK 245186 showed anti-inflammatory efficacy after topical application similar to the classical glucocorticoids, mometasone furoate and methylprednisolone aceponate. ZK 245186, however, exhibits a better safety profile with regard to growth inhibition and induction of skin atrophy after long-term topical application, thymocyte apoptosis, hyperglycaemia and hepatic tyrosine aminotransferase activity.


CONCLUSIONS
ZK 245186 is a potent anti-inflammatory compound with a lower potential for side effects, compared with classical glucocorticoids. It represents a promising drug candidate and is currently in clinical trials.
Schäcke
H
H
Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany. heike.schaecke@bayerhealthcare.com
Zollner
T M
TM
Döcke
W D
WD
Rehwinkel
H
H
Jaroch
S
S
Skuballa
W
W
Neuhaus
R
R
May
E
E
Zügel
U
U
Asadullah
K
K
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D007249:Inflammation / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D000439:Pentanols / Q000008:administration & dosage / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D012680:Sensitivity and Specificity; D012867:Skin / Q000187:drug effects*; D012871:Skin Diseases / Q000188:drug therapy*
D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D000439:Pentanols; D011804:Quinolines; C546413:R-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(((2-methyl-5-quinolyl)amino)methyl)pentan-2-ol; D011965:Receptors, Glucocorticoid