Discovery of a Potent
Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors
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Abstract
Inhibition of MK2 has been shown to offer advantages
over that of p38 MAPK in the development of cures for inflammatory
diseases such as arthritis. P38 MAPK knockout in mice was lethal,
whereas MK2-null mice demonstrated strong inhibition of disease progression
in collagen-induced arthritis and appeared normal and viable. However,
it is challenging to develop ATP-competitive MK2 inhibitors due to
high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors
interact and bind to the kinase in a mode independent of ATP concentration,
which could provide better selectivity and cellular potency. Therefore,
it is desirable to identify non-ATP-competitive MK2 inhibitors. Through
structure optimization of lead compound <b>1</b>, a novel series
of dihydrooxadiazoles was discovered. Additional structure–activity
relationship (SAR) study of this series led to the identification of compound <b>38</b> as a non-ATP-competitive MK2 inhibitor with potent enzymatic
activity and good cellular potency. The SAR, synthesis, and biological
data of dihydrooxadiazole series are discussed