Abstract
A novel
series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal
kinase) inhibitors were discovered and developed. Structure–activity
relationships (SARs) were systematically developed utilizing biochemical
and cell based assays and in vitro and in vivo drug metabolism and
pharmacokinetic (DMPK) studies. Through the optimization of lead compound
1
, several potent and selective JNK inhibitors with high oral
bioavailability were developed. Inhibitor
13
was a potent
JNK3 inhibitor (IC
50
= 15 nM), had high selectivity against
p38 (IC
50
> 10 μM), had high potency in functional
cell based assays, and had high stability in human liver microsome
(
t
1/2
= 76 min), a clean CYP-450 inhibition
profile, and excellent oral bioavailability (%
F
=
87). Moreover, cocrystal structures of compounds
13
and
22
in JNK3 were solved at 2.0 Å. These structures elucidated
the binding mode (Type-I binding) and can pave the way for further
inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition.
