title: Design, synthesis, and biological evaluation of aminopyrazine derivatives as inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2).
abstract: Several series of novel non-thiourea-containing aminopyrazine derivatives were designed based on the MK-2 inhibitors 1-(2-aminopyrazin-3-yl)methyl-2-thioureas. These compounds were synthesized and evaluated for their inhibitory activity against MK-2 enzyme in vitro. Compounds with low micromolar to sub-micromolar IC50 values were identified, and several compounds were also found to be active in suppressing the lipopolysaccharide (LPS)-stimulated TNFα production in THP-1 cells with minimum shift compared to their enzyme activity.
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States. Electronic address: songnian.lin@merck.com.
authors.forename: Songnian
authors.initials: S
authors.lastname: Lin
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Sunita
authors.initials: S
authors.lastname: Malkani
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lombardo
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chapman
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Thompson
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Wen Xiao
authors.initials: WX
authors.lastname: Zhang
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Ruixiu
authors.initials: R
authors.lastname: Wang
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Rose M
authors.initials: RM
authors.lastname: Cubbon
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'Neill
authors.affiliation: Early Development and Discovery Science, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
mesh_terms: D002460:Cell Line; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011719:Pyrazines; C079424:2-aminopyrazine; D019950:Mitogen-Activated Protein Kinase 1
keywords: Aminopyrazine; Guanidine; Inflammation; MAPKAP kinase 2; MK-2; Rheumatoid arthritis; TNFα; Thiourea replacement