title: Optimized protein kinase Cθ (PKCθ) inhibitors reveal only modest anti-inflammatory efficacy in a rodent model of arthritis.
abstract: We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.
authors.affiliation: AbbVie Bioresearch Center , 381 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: George
authors.forename: Eric C
authors.initials: EC
authors.lastname: Breinlinger
authors.forename: Maria A
authors.initials: MA
authors.lastname: Argiriadi
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jianfei
authors.initials: J
authors.lastname: Wang
authors.forename: Pratima
authors.initials: P
authors.lastname: Bansal-Pakala
authors.forename: David B
authors.initials: DB
authors.lastname: Duignan
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: QingYu
authors.initials: Q
authors.lastname: Lang
authors.forename: Scott
authors.initials: S
authors.lastname: Mittelstadt
authors.forename: Lian
authors.initials: L
authors.lastname: Rundell
authors.forename: Annette
authors.initials: A
authors.lastname: Schwartz
authors.forename: Jiakang
authors.initials: J
authors.lastname: Sun
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D007376:Interleukin-2; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta