New azolidinediones as inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties

Citation
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
Citations number
48
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
43
Issue
5
Year of publication
2000
Pages
995 - 1010
Database
ISI
SICI code
0022-2623(20000309)43:5<995:NAAIOP>2.0.ZU;2-H
Abstract
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.