Chemistry Reference
In-Depth Information
Table 4.6 Pharmacokinetic comparison of benzyoxyphenyl derivative 15a to
2-phenylquinolinyl derivative 17.
a
Compound
15a
17
Dose (mg kg
1
)
iv
1
5
Vehicle
b
A
C
C
max
(mM)
0.52
8.67
Terminal t
1/2
(h)
0.63
0.80
V
ss
(L kg
1
)
4.02
1.38
Cl (mLmin
1
kg
1
)
215
41.0
Dose (mg kg
1
)
50
c
Oral
5
50
5
50
50
Vehicle
b
B
B
B
B CD
C
max
(mM)
0.13
2.22
0.55
3.93
9.66
11.35
Terminal t
1/2
(h)
1.56
2.56
1.79
N/C
2.02
2.46
AUC
0-last
(ng hmL
1
)
76
1211
454
4954
10318
12554
%F
20
34
22
24
51
77
a
Cl
¼
clearance, V
ss
¼
volume of distribution at steady state, t
2
¼
elimination half-life,
C
max
¼
maximum measured plasma concentration, C
24h
¼
plasma concentration at 24 h, AUC
0-
last
¼
area under the concentration-time curve extrapolated to the last measured sampling time, N/
C
¼
not calculated, %F
¼
oral bioavailability.
b
Vehicle: (A) PEG 400 50% v/v in water, (B) 50:50 v/v PEG 400:citric acid 5% w/v, (C) pH 2 saline
at a dosing volume of 4mLkg
1
, (D) water.
c
Bis-HCl salt of parent compound.
formulated in water (or compound 17 as the free base formulated in pH 2
saline) provided better overall PK properties than formulating the free base in
50% v/v PEG 400:citric acid 5% w/v.
With significant improvements in both target potency and PK properties,
efforts were then focused exclusively on the quinolinyl series.
35-39
The overall
SAR was similar to that observed in the benzyloxy series and was supported by
an IGF-1R co-crystal structure with the advanced lead, PQIP (Figure 4.5),
which confirmed the key binding interactions as noted with the earlier IR/
benzyloxyphenyl-derived imidazopyrazine co-crystal structure.
40
A few key
SAR/SBD highlights include the following (Figure 4.4): (1) Substitution on the
8-amino moiety was disfavored since such substitution would interfere with
critical hinge interactions. (2) The C2 position of the quinoline ring showed a
strong preference for an unsubstituted phenyl ring over smaller alkyl groups
(i.e. methyl or ethyl), heteroaryl groups, or hydrogen. In the case of replace-
ment of the terminal phenyl ring with H, a complete loss in IGF-1R activity
(IC
50
4 10 mM) was observed. This complete loss in activity can be rationalized
based on the binding mode, as the space occupied by the terminal phenyl ring
cannot be fully occupied by hydrophobic collapse of the nearby protein resi-
dues. (3) The substituent at C3 of the imidazopyrazine ring occupied the ribose
binding pocket and influenced both potency and PK properties. (4) The qui-
nolinyl moiety was critical, as replacement with naphthyl resulted in a complete
loss in IGF-1R activity (IC
50
410 mM). The significant loss in potency was
attributed to the loss of the H-bond acceptor to K1033.
With the SAR from the quinolinyl series corresponding to that observed in
the earlier BnOC
6
H
4
series, efforts shifted towards further expanding the SAR
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