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R
N
O
N
N
O
O
N
H
2
N
CN
NH
O
CN
H
R
NH
2
H
O
R
R
27
(
syn
)
28
(
anti
)
29
30
Syn
oreintation favored with:
- increased steric bulk at R
- cis-4,5-fused cyclopropyl substitution
Figure 1.6
Factors determining syn versus anti orientation of the methano-nitrilo-
pyrrolidine chemotype.
favorably preserved in the cis-4,5-methano core (e.g. 24). These and other data
suggested that increased steric and lipophilic bulk at the P2 position of the
inhibitor (e.g. ethyl vs. isobutyl vs. tert-butyl, etc.) enhanced both in vitro
potency as well as solution stability. A similar trend was also observed by the
Ferring Research group in the simple nitrilo-pyrrolidine series.
34
Clearly both the steric bulk of the P2 side-chain and the cyclopropyl fusion
on the pyrrolidine ring cooperatively enhanced comformational stability.
Computational analyses later demonstrated that, primarily because of van der
Waals interactions, increasing the size of the side-chain R (Figure 1.6)
disfavored the anti orientation 28 required for irreversible intramolecular
cyclization to the inactive products 29 and 30. For example, where R is Me
versus tert-butyl, the DDH between the anti (28) and syn (27) orientations
were calculated to be 0.8 kcal mol
1
. Furthermore, addition of the cis-4,5-
cyclopropyl moiety also disfavors adoption of the anti orientation by an
additional 0.6 kcal mol
1
as compared to the unsubstituted nitrilo-pyrrolidine
ring. Thus, by combining these conformational elements, we were able to
identify novel inhibitors of DPP4 with high in vitro potency and enhanced
solution stability.
Compound 24 represented a major breakthrough in the chemistry program.
Profiling of this lead demonstrated a low potential for off-target liabilities
[hERG inhibition, cytochrome P450 (CYP450) inhibition, broad receptor
screening, etc.], as well as favorable pharmacokinetic properties in the rat
(F
¼
77%, t
1/2
¼
2.8 h). Additionally, compound 24 was ecacious in Zucker
fa/fa
rats, reducing glucose AUC in an acute oGTT (ED
50
¼
3.3mg kg
1
, glucose
challenge 30 min post-dose) when compared to vehicle control. While the
duration of action of 24 was not particularly long (ED
50
¼
92mg kg
1
, glucose
challenge 5 h post-dose), the in vivo potency was still significantly greater
than that of the literature thiazolidine lead 9 (ED
50
¼
38mg kg
1
, glucose chal-
lenge 30min post-dose). On the basis of these findings, additional staff were
assigned to the program to permit a detailed and robust exploration of the
structure-activity relationship (SAR), primarily focusing on further modifica-
tions at P2.
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