Prodrug delivery of novel PTP1B inhibitors to enhance insulin signalling.
A growing percentage of the population is resistant to two key hormones - insulin and leptin - as a result of increased obesity, often leading to significant health consequences such as type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of signalling by both of these hormones, so that inhibitors of this enzyme may provide promise for correcting endocrine abnormalities in both diabetes and obesity. As with other tyrosine phosphatases, identification of viable drug candidates targeting PTP1B has been elusive because of the nature of its active site. Beginning with novel phosphotyrosine mimetics, we have designed some of the most potent PTP1B inhibitors. However, their highly acidic structures limit intrinsic permeability and pharmacokinetics. Ester prodrugs of these inhibitors improve their drug-like properties with the goal of delivering these nanomolar inhibitors to the cytoplasm of cells within target tissues. In addition to identifying prodrugs that is able to deliver active drugs into cells to inhibit PTP1B and increase insulin signalling, these compounds were further modified to gain a variety of cleavage properties for targeting activity in vivo. One such prodrug candidate improved insulin sensitivity in ob/ob mice, with lowered fasting blood glucose levels seen in the context of lowered fasting insulin levels following 4 days of intraperitoneal dosing. The results presented in this study highlight the potential for design of orally active drug candidates targeting PTP1B, while also delineating the considerable challenges remaining.
Erbe
D V
DV
Departments of Metabolic Diseases and Chemical Sciences, Wyeth Research, Cambridge, MA 02140, USA. derbe@wyeth.com
Klaman
L D
LD
Wilson
D P
DP
Wan
Z-K
ZK
Kirincich
S J
SJ
Will
S
S
Xu
X
X
Kung
L
L
Wang
S
S
Tam
S
S
Lee
J
J
Tobin
J F
JF
D000284:Administration, Oral; D000818:Animals; D032701:Biomimetics; D001786:Blood Glucose / Q000032:analysis; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D005215:Fasting; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects
D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1