Ms. Malamas et al., New azolidinediones as inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties, J MED CHEM, 43(5), 2000, pp. 995-1010
Insulin resistance in the liver and peripheral tissues together with a panc
reatic cell defect are the common causes of type 2 diabetes. It is now appr
eciated that insulin resistance can result from a defect in the insulin rec
eptor signaling system, at a site post binding of insulin to its receptor.
Protein tyrosine phosphatases (PTPases) have been shown to be negative regu
lators of the insulin receptor. Inhibiton of PTPase may be an effective met
hod in the treatment of type 2 diabetes. A series of azolidinediones has be
en prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several
compounds were potent inhibitors against the recombinant rat and human PTP1
B enzymes with submicromolar IC50 values. Elongated spacers between the azo
lidinedione moiety and the central aromatic portion of the molecule as well
as hydrophobic groups at the vicinity of this aromatic region were very im
portant to the inhibitory activity. Oxadiazolidinediones 87 and 88 and the
corresponding acetic acid analogues 119 and 120 were the best h-PTP1B inhib
itors with IC50 values in the range of 0.12-0.3 mu M. Several compounds nor
malized plasma glucose and insulin levels in the ob/ob and db/db diabetic m
ouse models.