title: Structure-activity relationship and pharmacokinetic studies of sotrastaurin (AEB071), a promising novel medicine for prevention of graft rejection and treatment of psoriasis.
abstract: Protein kinase C (PKC) isotypes have emerged as key targets for the blockade of early T-cell activation. Herein, we report on the structure-activity relationship and the detailed physicochemical and in vivo pharmacokinetic properties of sotrastaurin (AEB071, 1), a novel maleimide-based PKC inhibitor currently in phase II clinical trials. Most notably, the preferred uptake of sotrastaurin into lymphoid tissues is an important feature, which is likely to contribute to its in vivo efficacy.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel CH-4002, Switzerland. juergen.wagner@novartis.com
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wagner
authors.forename: Peter
authors.initials: P
authors.lastname: von Matt
authors.forename: Bernard
authors.initials: B
authors.lastname: Faller
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Cooke
authors.forename: Rainer
authors.initials: R
authors.lastname: Albert
authors.forename: Richard
authors.initials: R
authors.lastname: Sedrani
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Wiegand
authors.forename: Christian
authors.initials: C
authors.lastname: Jean
authors.forename: Christian
authors.initials: C
authors.lastname: Beerli
authors.forename: Gisbert
authors.initials: G
authors.lastname: Weckbecker
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Evenou
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zenke
authors.forename: Sylvain
authors.initials: S
authors.lastname: Cottens
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011565:Psoriasis / Q000188:drug therapy*; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D011493:Protein Kinase C