In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part I.
Pyrrolo[2,3-f]isoquinoline based amino acids, tetracyclic lactams and cyclic ketone analogues are described as novel MK2 inhibitors with IC(50) as low as 5nM and good selectivity profiles against a number of related kinases including ERK, p38alpha and JNKs. TNFalpha release was suppressed from human peripheral blood mononuclear cells (hPBMCs), and a representative compound inhibited LPS induced TNFalpha release in mice illustrating the potential of this series to provide orally active MK2 inhibitors.
Revesz
Laszlo
L
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. laszlo.revesz@pharma.novartis.com
Schlapbach
Achim
A
Aichholz
Reiner
R
Feifel
Roland
R
Hawtin
Stuart
S
Heng
Richard
R
Hiestand
Peter
P
Jahnke
Wolfgang
W
Koch
Guido
G
Kroemer
Markus
M
Möbitz
Henrik
H
Scheufler
Clemens
C
Velcicky
Juraj
J
Huppertz
Christine
C
D000284:Administration, Oral; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007546:Isoquinolines / Q000737:chemistry; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D000596:Amino Acids; D006576:Heterocyclic Compounds, 4 or More Rings; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D007659:Ketones; D007769:Lactams; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2; C039109:isoquinoline