title: Novel, potent and selective inhibitors of protein kinase C show oral anti-inflammatory activity.
abstract: Clarification of the precise role of protein kinase C (PKC) in cellular functional responses has been hampered by a lack of potent, selective inhibitors. The structural lead provided by staurosporine, a potent but non-selective protein kinase (PK) inhibitor, was used to derive a series of bis(indolyl)maleimides of which the most potent, Ro 31-8425 (I50: PKC = 8 nM) showed 350-fold selectivity for PKC over cAMP-dependent protein kinase. Ro 31-8425 antagonised cellular processes triggered by phorbol esters (potent, specific PKC activators) and inhibited the allogeneic mixed lymphocyte reaction, suggesting a role for PKC in T-cell activation. Methylation of the primary amine in Ro 31-8425 produced an analogue. Ro 31-8830 which, when administered orally, produced a dose-dependent inhibition of a phorbol ester-induced paw oedema in mice (minimum effective dose = 15 mg/kg). Ro 31-8830 also selectively inhibited the secondary inflammation in a developing adjuvant arthritis model in the rat. The results presented here suggest that these selective inhibitors of PKC may have therapeutic value in the treatment of T-cell-mediated autoimmune diseases.
authors.affiliation: Research Centre, Roche Products Ltd., Welwyn Garden City, Herts., UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Nixon
authors.forename: J
authors.initials: J
authors.lastname: Bishop
authors.forename: D
authors.initials: D
authors.lastname: Bradshaw
authors.forename: P D
authors.initials: PD
authors.lastname: Davis
authors.forename: C H
authors.initials: CH
authors.lastname: Hill
authors.forename: L H
authors.initials: LH
authors.lastname: Elliott
authors.forename: H
authors.initials: H
authors.lastname: Kumar
authors.forename: G
authors.initials: G
authors.lastname: Lawton
authors.forename: E J
authors.initials: EJ
authors.lastname: Lewis
authors.forename: M
authors.initials: M
authors.lastname: Mulqueen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy; D005260:Female; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D008301:Maleimides; D010703:Phorbol Esters; C071924:Ro 31-8425; C076005:Ro 31-8830; D011493:Protein Kinase C