Discovery of <i>N</i>-((4-([1,2,4]Triazolo[1,5-<i>a</i>]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1<i>H</i>-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of TGF-β Type I Receptor Kinase as Ca

다국어 초록 (Multilingual Abstract)

<P>A series of 2-substituted-4-([1,2,4]triazolo[1,5-<I>a</I>]pyridin-6-yl)-5-(6-methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), <B>6</B>. Combination of replacement of a quinoxalin-6-yl moiety of <B>6</B> with a [1,2,4]triazolo[1,5-<I>a</I>]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a <I>o</I>-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The <B>12b</B> (EW-7197) inhibited ALK5 with IC<SUB>50</SUB> value of 0.013 μM in a kinase assay and with IC<SUB>50</SUB> values of 0.0165 and 0.0121 μM in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of <B>12b</B> using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with <B>12b</B>·HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng × h/mL and maximum plasma concentration (<I>C</I><SUB>max</SUB>) of 1620 ng/mL. Rational optimization of <B>6</B> has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor <B>12b</B>.</P><P><B>Graphic Abstract</B>
<IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2014/jmcmar.2014.57.issue-10/jm500115w/production/images/medium/jm-2014-00115w_0012.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm500115w'>ACS Electronic Supporting Info</A></P>