 |
| |
| |
|
Diabetes is a major worldwide disease.
The International Diabetes Foundation estimated that,
in 2005, there were 194 million adults with diabetes
worldwide, an increase of over 40% since 1995. Approximately
90% of diabetics, or 175 million people, suffer from
type 2 diabetes, the adult-onset form of the disease.
Type 2 diabetes is characterized by inadequate response
to insulin and/or inadequate secretion of insulin
as blood glucose levels rise. Although deaths due
to cancer, stroke, and cardiovascular disease are
declining, the death rates due to diabetes have increased
by about 30% in the past 12 years, and life expectancy
for persons with diabetes is approximately 15 years
less than in those who do not have diabetes. Therapies
for type 2 diabetes are directed toward correcting
the body's inadequate response with oral and injectable
medications, or directly modifying insulin levels
by injection of insulin or insulin analogs. The worldwide
market for diabetes medications exceeded $10 billion
and oral anti-diabetes drugs exceeded $6 billion in
2004.
The Simbiosys diabetes discovery platform consists
of assaying solutions for a portfolio of clinically
validated as well as emerging therapeutic targets.
|
 |
PTP1B
Inhibitors |
| |
Several
protein tyrosine phosphatases (PTPs), including
PTPa, PTP-LAR, and PTP-1B, have been implicated
as negative regulators of the insulin signaling
pathway. PTP1B is involved in insulin and leptin
signaling and is the primary mechanism for down-regulating
both the insulin and leptin receptor signaling
pathways. Studies have shown that animals deficient
in PTP1B improve glucose regulation and lipid
profiles, and resist weight gain when treated
with a high fat diet. Evidences have helped
validate PTP-1B as a potential therapeutic target
in the treatment of diabetes type 2 and obesity.
Several pharmaceutical companies are pursuing
the development of PTP1B inhibitors with the
most advanced candidates now entering phase
I and II trials.
|
| |
|
|
Dipeptidyl
Peptidase-IV (DPP-IV) Inhibitors |
| |
A
novel mechanism for the treatment of type 2
diabetes is DPP-IV inhibitors. They decrease
the breakdown of GLP-1 by extending the half-life
of endogenous GLP-1. Investigational DPP-IV
inhibitors offer an advantage over other novel
therapies (e.g., GLP-1 agonists and amylin analogs)
since they can be administered orally. There
are various DPP-IV inhibitors in Phase I, II,
and III trials. DPP-IV is a member of a family
of serine peptidases that includes quiescent
cell praline dipeptidases (QPP), DPP8, and DPP9.
In studies, DPP-8/9 inhibitors produced alopecia,
thrombocytopenia, reticulocytopenia, enlarged
spleen, multiorgan histopathological changes,
and even mortality. Therefore, the selectivity
of clinical candidates to DPP-IV over DPP-8/9
is important to an optimal safety profile.
|
|
|
|
|
| |
| |
|
|
|
