Chemistry Reference
In-Depth Information
activation of intracellular signal transduction pathways and cell-cell interac-
tion in addition to its peptidase enzymatic activity.
18
It is widely believed that
the signaling function of DPP4/CD26 is distinct from its enzymatic function.
The concept of generating targeted protease/peptidase inhibitors as thera-
peutic agents is well documented in the literature.
19
In the majority of cases,
selective enzyme inhibitors have been used to prevent the conversion of an
endogenous ''non-functional'' peptide/protein precursor (e.g. angiotensin I) to
a physiologically active peptide/protein (e.g. angiotensin II), thereby attenu-
ating formation of the protagonist bio-active enzyme product to effect ameli-
oration of the disease state. Use of such approaches has led to marketed drugs
for numerous indications, including ACE and renin inhibitors for hyperten-
sion,
20
HIV protease inhibitors for AIDS,
21
and thrombin inhibitors for
DVT.
22
Less prevalent are approaches targeting proteases/peptidases that
degrade endogenous substrates which are known to exert a beneficial effect. For
example, neutral endopeptidase (NEP) proteolytically degrades the endogen-
ous vasodilator atrial natriuretic peptide (ANP) to inactive fragments. By
retarding this degradation, NEP inhibitors have found use in the treatment of
hypertension.
23
In common with NEP, where inhibition of protease mediated
protein degradation was the pharmacological objective, BMS and several other
research groups engaged in the search for DPP4 inhibitors to maximize the
beneficial effects of endogenously released GLP-1.
1.4 Early Inhibitors of DPP4
To jump-start the BMS DPP4 chemistry program, the group was able to
capitalize on groundwork laid in the mid-late 1990's when several potent
inhibitors of DPP4/CD26 were reported that could be classified as either
''irreversible'' or ''reversible'', depending on the mechanism of inhibition
(Figures 1.2 and 1.3). Hydroxamates such as 4 were proposed to be both
substrates and inhibitors of DPP4, presumably via direct covalent modification
of the enzyme through the active-site serine residue (Ser630).
24
Phosphate-
based inhibitors such as 5 were also reported to undergo covalent addition to
DPP4 but exhibited weak potency.
25
The interesting boronate-based inhibitors
(e.g. 6), originally advanced by the Tufts University and Boehringer Ingelheim
groups, exhibited exceptionally high inhibitory activity in vitro, presenting
Me
N
H
2
N
Me
N
O
O
O
P
O
NO
2
N
N
O
OH
H
2
N
H
2
N
B
N
OH
B
O
Cl
O
O
OH
H
H
HO
H
O
O
4
5
6
7
Cl
Figure 1.2
Early examples of ''irreversible'' DPP4 inhibitors.
Search WWH ::
Custom Search