Biomedical Engineering Reference
In-Depth Information
1.7.1 Targeting Enzymatic Function
Numerous diseases have been targeted for therapeutic treatment via DP4
inhibition including rheumatoid arthritis, multiple sclerosis, psoriasis, wound
healing, anxiety, type II diabetes and cancer. Successful inhibition of DP4 for
the treatment of type II diabetes has been clearly clinically validated with
several DP4 inhibitors developed by different pharmaceutical companies for the
treatment of type II diabetes now available on the market or awaiting approval
(Table 1.3). Targeted inhibition of DP4 as a therapeutic option is currently
being investigated in a number of other disorders, particularly those of an
inflammatory nature such as arthritis, skin inflammation, multiple sclerosis,
and inflammatory bowel disease. 237 Taking into account the overlap of sub-
strates between DP4 and aminopeptidase N, a novel dual targeting therapy is
also being investigated as a therapeutic concept in the treatment of inflam-
matory disease and acne pathogenesis. 134,238 To attain clinical approval, the
specificity, safety, and ecacy of these inhibitors need to be ensured so that off-
target inhibition is not an issue. Lankas et al. also found that a number of DP4
inhibitors including L -allo-isoleucyl thiazolidide, Lys[Z(NO 2 )]-pyrrolidide
(LZNP) previously used in several studies implicating the roles of DP4 in
immune function, were actually more potent inhibitors of DP8/9 and DP2
(IC 50(LZNP) : DP8 o DP9 oo DP2 o DP4 ΒΌ 154 o 165 oo 1210 o 1300). 11 Thus, it
is highly likely that some of the reported effects of these inhibitors on immune
function are due to off-target inhibition of DP8/9 or DP2 rather than the
reported DP4. Lankas et al. also demonstrated that Val-boroPro, used in
clinical trials as discussed below, is a highly non-selective DP inhibitor with IC 50
values for DP4 o DP8 o DP9 oo DP2
PEP o FAP (expressed in nmol l -1 ) being
o 4, 4, 11, 310, 390, and 560 respectively. 11
Table 1.3 DP4 inhibitors for the treatment of type II diabetes.
Oral inhibitor
Trade name Current status
Sitagliptin 242-244
Januvia s
Used in 440 countries
FDA approved in 2006
EMEA approved in 2007
Saxagliptin 245-247
Onglyza s
Bristol-Myers Squibb &
Astra Zeneca
FDA approved in 2009
Vildagliptin 248-250
Galvus s
EMEA approved in 2007
Alogliptin 251
Takeda Pharmaceutical
FDA application sus-
pended as of 2009,
insucient data
Linagliptin 252,253
Ondero s
Phase III clinical trials a
Boehringer Ingelheim
Pharma GmbH and Co.
Phenomix Corporation Dutogliptin 254,255
Phase III clinical trials a
Phase III clinical trials a
LG Life Sciences
a At time of publication.
FDA, Food and Drug Administration (USA); EMEA, European Medicines Agency; LG, Life's
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