title: Discovery of selective glucocorticoid receptor modulator MK-5932.
abstract: A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA. christopher_bungard@merck.com
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bungard
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Manikowski
authors.forename: James J
authors.initials: JJ
authors.lastname: Perkins
authors.forename: Chang
authors.initials: C
authors.lastname: Bai
authors.forename: Philip E
authors.initials: PE
authors.lastname: Brandish
authors.forename: Danielle H
authors.initials: DH
authors.lastname: Euler
authors.forename: James C
authors.initials: JC
authors.lastname: Hershey
authors.forename: Azriel
authors.initials: A
authors.lastname: Schmidt
authors.forename: Yulin
authors.initials: Y
authors.lastname: Fang
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Norcross
authors.forename: Tom H
authors.initials: TH
authors.lastname: Rushmore
authors.forename: Charles D
authors.initials: CD
authors.lastname: Thompson
authors.forename: Robert S
authors.initials: RS
authors.lastname: Meissner
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D019149:Bioreactors; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003640:Dealkylation; D003872:Dermatitis / Q000188:drug therapy; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007313:Insecta; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009251:NADPH-Ferrihemoprotein Reductase