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toxicities. The Merck findings undoubtedly influenced the inhibitor design
efforts of nearly every DPP4 discovery program in the industry, resulting in a
proliferation of varied chemotypes with ''atypical'' protease inhibitor structural
features as compared to the more dipeptidic motifs shared by saxagliptin and
vildagliptin.
Several groups attempting to better understand the consequences of DPP8/9
inhibition in animals have subsequently published their findings using more
structurally diverse inhibitors of DPP8/9 as tool molecules. Rosenblum et al.
recently showed that treatment of dogs with high doses of a selective, cell-
permeable DPP4/8/9 inhibitor (producing extensive inhibition of DPP4/8/9 in
GI tissues) did not afford toxicological responses similar to those observed by
Merck with their tool compounds.
59
In a separate study, Chen et al. demon-
strated that repeated exposure (iv, QD for 14 days) of IG244, a potent and cell-
permeable DPP8/9 inhibitor, did not result in severe toxicity in rats, despite
complete DPP8/9 inhibition achieved with this inhibitor.
60
Additionally,
Burkey et al. demonstrated that chronic dosing of vildagliptin (achieving
plasma levels well above its K
i
for DPP8 and DPP9 inhibition) failed to reca-
pitulate the toxicity profile observed with the Merck DPP8/9 inhibitor.
61
Col-
lectively, these empirical studies offer little to mechanistically connect the
inhibition of DPP8 or DPP9 to a phenotype, and as such, the functional
consequences of DPP8 and DPP9 inhibition in animals and humans remains
unknown.
62
Thus, while DPP4 selectivity has become cemented as an intrinsic
component of most DPP4 inhibitor programs industry-wide, the need for
exquisitely high selectivity against the DPP8 and DPP9 proteases remains an
unproven concept in DPP4 inhibitor design.
1.12 Synthesis of Saxagliptin
The structural complexity of saxagliptin posed some synthesis development
challenges, in that the molecule possesses four asymmetric centers, including a
neopentyl carbon center, where only one of the stereochemical centers was
available through a commercially available chiral building block. However, the
team's willingness to employ challenging synthetic chemistry to solve medicinal
chemistry problems was key to the discovery of highly potent, more stable, and
patentable lead compounds. The discovery synthesis of saxagliptin, used to
prepare
100-200 g of material for pre-development work, was in need of
substantial optimization for large-scale production of this rather complex
molecule. In particular, the need to perform a zinc-mediated cyclopropanation
at low temperature with high diastereoselectivity, and the development of a
robust large-scale synthesis of the chiral adamantyl fragment, proved to be a
daunting task. The process chemistry group at BMS tackled each portion of this
molecule with creative solutions to provide an ecient and reproducible man-
ufacturing route. Key synthetic transformations are depicted in Figure 1.11, and
include: (1) a Reformatsky reaction of bromoadamantane with a silyl-protected
dichloroketene acetal, followed by oxidation and hydrolysis to give keto
B
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