Structure-Based Design of Active-Site-Directed, Highly Potent, Selective, and Orally Bioavailable Low-Molecular-Weight Protein Tyrosine Phosphatase Inhibitors

Protein tyrosine phosphatases constitute an important
class of
drug targets whose potential has been limited by the paucity of drug-like
small-molecule inhibitors. We recently described a class of active-site-directed,
moderately selective, and potent inhibitors of the low-molecular-weight
protein tyrosine phosphatase (LMW-PTP). Here, we report our extensive
structure-based design and optimization effort that afforded inhibitors
with vastly improved potency and specificity. The leading compound
inhibits LMW-PTP potently and selectively (Ki = 1.2 nM, >8000-fold selectivity). Many compounds exhibit
favorable drug-like properties, such as low molecular weight, weak
cytochrome P450 inhibition, high metabolic stability, moderate to
high cell permeability (Papp > 0.2 nm/s), and moderate to good
oral
bioavailability (% F from 23 to 50% in mice), and
therefore can be used as in vivo chemical probes to further dissect
the complex biological as well as pathophysiological roles of LMW-PTP
and for the development of therapeutics targeting LMW-PTP.