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Terminal Phenyl Ring
Unsubstituted phenyl preferred
Heteroaryls generally disfavored
Substituents generally disfavored
Phenyl > alkyl > hydrogen
C1 Substituent
Quinoline (X = N, Y = CH) > quinazoline (X
and Y = N) > naphthyl (X and Y = CH)
C3 Substituent
Y
X
NH
2
N
N
N
Critical mass required
Cycloalkyl > aryl/heteroaryl > alkyl > H
R substituents regulate DMPK properties
8-amino
R
Substitution not tolerated (i.e. methyl, acyl)
Figure 4.4
SAR summary of quinolinyl-derived imidazopyrazine IGF-1R inhibitors.
N
NH
2
PQIP: R =
N
N
N
N
N
N
AQIP: R =
CH
2
R
Figure 4.5
PQIP and AQIP.
around the imidazopyrazine C3 substituents with the aim of improving the
DMPK shortcomings of early leads, i.e. the high clearance associated with
cyclohexylamide 15a. As noted earlier, the substituents at C3 of the imidazo-
pyrazine ring occupy the ribose binding pocket of IGF-1R and also regulate the
overall DMPK properties of the molecule. While exploring the SAR in this
region, we discovered that unsubstituted cycloalkyl derivatives, such as com-
pound 18 (Scheme 4.3), were potent IGF-1R inhibitors but displayed poor
metabolic stability in the presence of liver microsomes, with an extraction
ratio
41
of 0.9 for both mouse and human (Table 4.7). PK analysis in mice
revealed that this in vitro instability in liver microsomes was reflected by a
clearance rate equal to the liver blood flow in mice (Cl
¼
90mLmin
1
kg
1
)
(Table 4.7). Following the oral administration of 100mg kg
1
of compound 18
in mice, both the parent compound and a major M
þ
16 metabolite were
detected in the plasma samples (Table 4.8). In vivo metabolite identification
studies determined that hydroxylation at the C3 position of the cyclobutyl ring
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