Chemistry Reference
In-Depth Information
With this background in mind, we sought to identify new targets which would
not only provide an ecacious alternative mechanism for lowering blood
glucose and HbA1c levels, but would also present an opportunity for achieving
a superior safety and tolerability profile when compared to current standards of
care. Ideally, such a drug would be suitable for combination with existing
agents, as poly-pharmacology with multiple OADs is emerging as the standard
treatment paradigm for type-2 diabetes therapy.
Glucagon like peptide-1 (GLP-1) is a 30-amino acid peptide incretin hor-
mone derived from processing of pro-glucagon and is secreted by the L-cells of
the intestinal mucosa in response to glucose stimulation. Since the early 1990's,
GLP-1 had been known to be a potent insulin secretagogue and glucagon
suppressor, with robust anti-diabetic and pro-satiety effects in diabetic
humans,
11,12
but efforts to advance GLP-1 itself as a pharmaceutical agent
were hampered by its extremely short pharmacokinetic half-life in vivo (plasma
t
1/2
E
2min). As a result, considerable effort in the drug discovery community
was expended toward the identification of small-molecule GLP-1 receptor
agonists that would capture the beneficial effects of GLP-1 while exhibiting oral
bioavailability and a superior pharmacokinetic duration of action. Unfortu-
nately, efforts to identify such small-molecule agonists have to date been
unsuccessful, due in part to a dearth of viable bona fide screening hits.
13
In light
of this shortcoming, a number of pharmaceutical and biotech companies have
advanced subcutaneously administered, peptide GLP-1 receptor agonists with
superior duration of action in vivo. Among the most advanced agents are
exenatide (Byetta
t
)
14
and liraglutide (Victoza
t
),
15
both of which have been
approved by regulatory agencies for the treatment of type-2 diabetes. While
these drugs are effective in lowering HbA1c and demonstrate a net beneficial
effect on weight gain and other CV risk factors, they require parenteral
administration (once or twice daily dosing), and patient uptake of these agents
has been limited despite their robust ecacy and promising safety profile.
1.3 Dipeptidyl Peptidase-4 as a Target for Diabetes
Treatment
While the advancement of orally active, small-molecule GLP-1 receptor ago-
nists remains elusive, another opportunity to modulate GLP-1 receptor activity
in vivo focused on preventing the degradation of endogenous GLP-1 with small-
molecule inhibitors of the primary peptidase responsible for the in vivo
degradation of GLP-1, dipeptidyl peptidase-4 (DPP4), a non-classical serine
protease.
16
Our initial interest in DPP4 inhibitors was piqued by a report from
Holst and Deacon, wherein the authors outlined a compelling argument for the
utility of DPP4 inhibition in the treatment of diabetes, primarily via the
potentiation of endogenous GLP-1.
17
DPP4 belongs to a family of aminodi-
peptidases and is both a cell surface and circulating enzyme. Historically, it had
also been identified as the lymphocyte cell surface marker CD26, and as such
DPP4/CD26 exhibits pharmacology related to cell membrane-associated
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