title: In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II.
abstract: Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC(50)<3 nM and inhibit the release of TNFalpha (IC(50)<0.3 microM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC(50)=0.05-0.23 microM), less potent in cells (IC(50)<1.1 microM), but show good oral absorption. Compound 13E (100mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score.
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. laszlo.revesz@pharma.novartis.com
authors.forename: Laszlo
authors.initials: L
authors.lastname: Revesz
authors.forename: Achim
authors.initials: A
authors.lastname: Schlapbach
authors.forename: Reiner
authors.initials: R
authors.lastname: Aichholz
authors.forename: Janet
authors.initials: J
authors.lastname: Dawson
authors.forename: Roland
authors.initials: R
authors.lastname: Feifel
authors.forename: Stuart
authors.initials: S
authors.lastname: Hawtin
authors.forename: Amanda
authors.initials: A
authors.lastname: Littlewood-Evans
authors.forename: Guido
authors.initials: G
authors.lastname: Koch
authors.forename: Markus
authors.initials: M
authors.lastname: Kroemer
authors.forename: Henrik
authors.initials: H
authors.lastname: Möbitz
authors.forename: Clemens
authors.initials: C
authors.lastname: Scheufler
authors.forename: Juraj
authors.initials: J
authors.lastname: Velcicky
authors.forename: Christine
authors.initials: C
authors.lastname: Huppertz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001384:Azetidines / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D001383:Azetidinecarboxylic Acid; D001384:Azetidines; D003521:Cyclopropanes; D055551:HSP27 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2; C082735:azetidine; C030797:cyclopropane