Novel Inhibitors of the MDM2-p53
Interaction Featuring
Hydrogen Bond Acceptors as Carboxylic Acid Isosteres
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Abstract
We
previously reported the discovery of potent and selective morpholinone
and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors
have in common a carboxylic acid moiety that engages in an electrostatic
interaction with MDM2-His96. Our continued search for potent and diverse
inhibitors led to the discovery of novel replacements for these acids
uncovering new interactions with the MDM2 protein. In particular,
using pyridine or thiazole as isosteres of the carboxylic acid moiety
resulted in very potent analogues. From these, AM-6761 (<b>4</b>) emerged as a potent inhibitor with remarkable biochemical (HTRF
IC<sub>50</sub> = 0.1 nM) and cellular potency (SJSA-1 EdU IC<sub>50</sub> = 16 nM), as well as favorable pharmacokinetic properties.
Compound <b>4</b> also shows excellent antitumor activity in
the SJSA-1 osteosarcoma xenograft model with an ED<sub>50</sub> of
11 mg/kg. Optimization efforts toward the discovery of these inhibitors
as well as the new interactions observed with the MDM2 protein are
described herein