2-Aminothiazole (
1) wa
s di
scovered a
s a novel Src family kina
se inhibitor template through
screening ofour internal compound collection. Optimization through
succe
ssive
structure-activity relation
ship iteration
sidentified analog
s 2 (Da
satinib, BMS-354825) and
12m a
s pan-Src inhibitor
s with nanomolar to
subnanomolarpotencie
s in biochemical and cellular a
ssay
s. Molecular modeling wa
s u
sed to con
struct a putative bindingmodel for Lck inhibition by thi
s cla
ss of compound
s. The framework of key hydrogen-bond interaction
spropo
sed by thi
s model wa
s in agreement with the
sub
sequent, publi
shed cry
stal
structure of
2 bound to
structurally
similar Abl kina
se. The oral efficacy of thi
s cla
ss of inhibitor
s wa
s demon
strated with
12m ininhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED
50 ~ 5 mg/kg) and in reducing TNFlevel
s in an acute murine model of inflammation (90% inhibition in LPS-induced TNF
s/gifchar
s/alpha.gif" BORDER=0> production whendo
sed orally at 60 mg/kg, 2 h prior to LPS admini
stration). The oral efficacy of
12m wa
s further demon
stratedin a chronic model of adjuvant arthriti
s in rat
s with e
stabli
shed di
sea
se when admini
stered orally at 0.3 and3 mg/kg twice daily. Da
satinib (
2) i
s currently in clinical trial
s for the treatment of chronic myelogenou
sleukemia.