Chemistry Reference
In-Depth Information
HO
N
N
H
2
N
H
2
N
CN
O
CN
O
R
2
R
1
R
3
33
DPP4 Ki = 7.4 nM
32
DPP4 Ki = 3.9 nM
R
N
N
H
CN
O
HO
in vivo
conversion
31
N
N
H
2
N
H
2
N
CN
O
CN
O
34
DPP4 Ki = 0.9 nM
3
DPP4 Ki = 1.3 nM
-High
in vitro
potency
-High
in vitro
potency
- Excellent
in vivo
efficacy & duration
-Excellent
in vivo
efficacy & duration
of action
- Poor oral exposure and short half life
of action
-Goodoralexposueandhalflife
Figure 1.8
Classical PK/PD disconnect in rats leads to hypothesis of active meta-
bolite generation in vivo, resulting in the discovery of saxagliptin.
enantiomerically pure P1 nitrilo-methanopyrrolidine fragment and the result-
ing diastereomers were chromatographically resolved.
From this effort emerged two compounds of particular interest, inhibitors 32
and 34 (Figure 1.8). In the case of 32, this compound demonstrated superior in
vivo ecacy and a sustained duration of response for inhibition of plasma
DPP4 in normal fasted SD rats at a dose of 4 mmol kg
1
(71% @ 30min post-
dose and 64% @ 4 h post-dose). Duration of the pharmacodynamic (PD)
response was particularly long when compared to compounds generated earlier
in the program. Intriguingly, this extended PD response was most often
observed in analogues containing a vinyl substituent (e.g. 32) at P2. Despite its
robust in vivo activity, compound 32 demonstrated low oral bioavailability
(5%) and a short half-life (t
1/2
¼
1.2 h) in rats. In contrast, the related saturated
analogue of 32 (vinyl replaced with ethyl) exhibited significantly higher bio-
availability (31%) and greater in vitro stability in rat and human liver micro-
somes, but a weaker response in the rat plasma DPP4 inhibition assay (despite
equivalent in vitro potency). The disconnect between the pharmacokinetic and
pharmacodynamic profile of 32 immediately suggested in vivo conversion to an
active metabolite possessing superior target potency and/or reduced clearance
profile. Based on this hypothesis, a variety of putative or surrogate hydr-
oxylated metabolites related to 32 were prepared. While unequivocal char-
acterization of 33 as an active metabolite of 32 was never established, the
activity of 33 mirrored that of 32 in the aforementioned PD model. While the
rat half-life of 33 (t
1/2
¼
1.3 h) was not significantly longer when compared to
that of 32, the absolute bioavailability increased 10-fold to 53%. A more
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