2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.
We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC(50) values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFalpha production in peripheral human monocytes.
Harris
Christopher M
CM
Abbott Laboratories, 100 Research Drive, Worcester, MA 01605-5314, USA.
Ericsson
Anna M
AM
Argiriadi
Maria A
MA
Barberis
Claude
C
Borhani
David W
DW
Burchat
Andrew
A
Calderwood
David J
DJ
Cunha
George A
GA
Dixon
Richard W
RW
Frank
Kristine E
KE
Johnson
Eric F
EF
Kamens
Joanne
J
Kwak
Silvia
S
Li
Biqin
B
Mullen
Kelly D
KD
Perron
Denise C
DC
Wang
Lu
L
Wishart
Neil
N
Wu
Xiaoyun
X
Zhang
Xiaolei
X
Zmetra
Tami R
TR
Talanian
Robert V
RV
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D000893:Anti-Inflammatory Agents; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2; C017205:2,4-diaminopyrimidine