Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas as potent inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2)

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 12, 2009, Pages 3238-3242

  Lin, Songnian ^a   Lombardo, Matthew ^a   Malkani, Sunita ^a   Hale, Jeffrey J ^a   Mills, Sander G ^a   Chapman, Kevin ^a   Thompson, James E ^a   Zhang, Wen Xiao ^a   Wang, Ruixiu ^a   Cubbon, Rose M ^a   O'Neill, Edward A ^a   Luell, Silvi ^a   Carballo Jane, Ester ^a   Yang, Lihu ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Aminopyrazine; Inflammation; MAPKAP kinase 2; MK 2; Rheumatoid arthritis; Thiourea; TNF

Indexed keywords

1 (2 AMINOPYRAZIN 3 YL)METHYL 2 THIOUREA DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE 1; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ARTICLE; DRUG ACTIVITY; DRUG SYNTHESIS; IC 50; INFLAMMATION; STRUCTURE ACTIVITY RELATION;

ANIMALS; CELL LINE, TUMOR; DRUG EVALUATION, PRECLINICAL; HUMANS; INFLAMMATION; INHIBITORY CONCENTRATION 50; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICE; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; THIOUREA; TUMOR NECROSIS FACTOR-ALPHA;

MUS;

EID: 65749101022     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.04.088     Document Type: Article

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27. To further support that the activity of these compounds was primarily due to MK-2 inhibition, the kinase selectivity of compounds 12b and 12d was investigated by screening against a panel of 33 kinases, including related MAPKAP kinases, p38 MAP kinases, CDK2, and other kinases associated with TNFα production. Of these kinases targeted for screening, only two had >70% inhibition at 1 μM for compound 12d (MK-5 and AMPK) and only four had >70% inhibition at 10 μM for compound 12b (RPS6KA1, RPS6KA5, AMPK, and LCK). The pharmacokinetic properties of these two compounds were evaluated in rat and the results are shown below in Table 7.
28. Modeling effort is being undertaken to further understand how these novel inhibitors interact with MK-2 in light of the recently available information on the binding site of MK-2 (see Refs. 7, 9a, 10a, and 12). The results of this study, together with the results of our continuous SAR effort to develop novel aminopyrazine-based non-thiourea MK-2 inhibitors, will be communicated separately in the near future.