title: 2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.
abstract: 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.
authors.affiliation: Abbott Laboratories, 100 Research Drive, Worcester, MA 01605-5314, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Harris
authors.forename: Anna M
authors.initials: AM
authors.lastname: Ericsson
authors.forename: Maria A
authors.initials: MA
authors.lastname: Argiriadi
authors.forename: Claude
authors.initials: C
authors.lastname: Barberis
authors.forename: David W
authors.initials: DW
authors.lastname: Borhani
authors.forename: Andrew
authors.initials: A
authors.lastname: Burchat
authors.forename: David J
authors.initials: DJ
authors.lastname: Calderwood
authors.forename: George A
authors.initials: GA
authors.lastname: Cunha
authors.forename: Richard W
authors.initials: RW
authors.lastname: Dixon
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Frank
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Joanne
authors.initials: J
authors.lastname: Kamens
authors.forename: Silvia
authors.initials: S
authors.lastname: Kwak
authors.forename: Biqin
authors.initials: B
authors.lastname: Li
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Mullen
authors.forename: Denise C
authors.initials: DC
authors.lastname: Perron
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Neil
authors.initials: N
authors.lastname: Wishart
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wu
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.forename: Tami R
authors.initials: TR
authors.lastname: Zmetra
authors.forename: Robert V
authors.initials: RV
authors.lastname: Talanian
mesh_terms: 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
chemical_list: 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