Novel benzofuran and benzothiophene biphenyls as inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties

Insulin resistance in the liver and peripheral tissues, together with a pan creatic cell defect, are the common causes of Type 2 diabetes. It is now ap preciated that insulin resistance can result from a defect in the insulin r eceptor signaling system, at a site post binding of insulin to its receptor . Protein tyrosine phosphatases (PTPases) have been shown to be negative re gulators of the insulin receptor. Inhibition of PTPases may be an effective method in the treatment of Type 2 diabetes. We have identified two novel s eries of benzofuran/benzothiophene biphenyl ore-acetic acids and sulfonyl-s alicylic acids as potent inhibitors of PTP1B with good oral antihyperglycem ic activity. To assist in the design of these inhibitors, crystallographic studies have attempted to identify enzyme inhibitor interactions. Resolutio n of crystal complexes has suggested that the inhibitors bind to the enzyme active site and are held in place through hydrogen bonding and van der Waa ls interactions formed within two hydrophobic pockets. In the ore-acetic ac id series, hydrophobic substitutents at position-2 of the benzofuran/benzot hiophene biphenyl framework interacted with Phe182 of the catalytic site an d were very critical to the intrinsic activity of the molecule. The hydroph obic region of the catalytic-site pocket was exploited and taken advantage by hydrophobic substituents at either the or-carbon or the ortho aromatic p ositions of the ore-acetic acid moiety. Similar ortho aromatic substitution s on the salicylic acid-type inhibitors had no effect, primarily due to the different orientation of these inhibitors in the catalytic site. The most active inhibitors of both series inhibited recombinant human PTP1B with pho sphotyrosyl dodecapeptide TRDI(P)YETD(P)Y(P)YRK as the source of the substr ate with IC50 values in the range of 20-50 nM. Compound 68 was one of the m ost active compounds in vivo, normalizing plasma glucose levels at the 25 m g/kg dose (po) and the 1 mg/kg dose tip). Compound 68 was also selective ag ainst several other PTPases.