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In-Depth Information
S
H
N
N
N
N
H
N
N
N
H
2
N
H
2
N
H
2
N
CN
O
X
CN
O
O
O
8
9
10
11
(X = CF3)
12
(X = CN)
N
N
O
O
O
NH
N
H
H
14
13
Figure 1.3
Early examples of ''reversible'' DPP4 inhibitors
themselves as ''transition-state'' inhibitors which presumably form tetrahedral
boronate esters involving the Ser630 hydroxyl group.
26-28
As such, many of
these compounds exhibited slow tight-binding kinetics with K
off
rates of several
days (versus seconds/minutes with non-covalently bound inhibitors). However,
these compounds also suffered from poor solution stability arising from
intramolecular cyclization of the terminal primary amine with the boronate,
affording an inactive product (e.g. 7). The propensity of compounds of this
chemotype to undergo internal cyclization limited their viability as drug
candidates.
Due to the uncertain risks associated with advancing irreversible inhibitors as
drug candidates, the team viewed the reversible inhibitors exploited by the
Mount Sinai, Probiodrug, Ferring Research, and Novartis scientific teams as
more attractive starting points for a lead finding effort (Figure 1.3). Probiodrug
had described simple Ile-pyrrolidides (8) and Ile-thiazolidides (9, later advanced
to the clinic by Merck and Probiodrug as P32/98) which exhibited in vitro
potency in the nanomolar range, were chemically stable, and, in the case of 9,
demonstrated glucose area under the curve (AUC) reductions in Zucker
fa/fa
rats
in an oral glucose tolerance test (oGTT).
29-31
Reports from Li et al. at Mount
Sinai highlighted early examples of nitrilo-pyrrolidines specifically designed as
inhibitors of DPP4.
32
Equally intriguing was the work described by Ferring in
which nitrilo-pyrrolidines such as 10 were identified as exceptionally potent
inhibitors of the enzyme.
33,34
Initially targeted as agents for immunomodula-
tion (via CD26 inhibition), these compounds represented ''drug-like'' scaffolds
and exhibited exceptional inhibitory potency. Additionally, a contempo-
raneous patent application from Novartis
35
described the structure of com-
pound 11 (a related analogue 12 would later be disclosed as Novartis' first
clinical compound, DPP-728)
36
and its ability to increase plasma insulin in
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