Chemistry Reference
In-Depth Information
44 (3 nM vs. 14 nM), while for the trifluoromethyl-substituted series, the
methanesulfonamide 50 has similar potency to the amide 51 (5 nM vs. 9nM).
This shows that there is cross-talk between the benzylamine ring and phenoxy
ring SARs.
While mono N-alkylation of either the amides or sulfonamides was tolerated,
dialkylation was detrimental to both activity and selectivity. For example, the
tertiary amide 53 is 4-fold less active than the secondary amide 52 (IC
50
¼
39
nM vs. 11 nM) and only has 11-fold selectivity over NRI. Similarly, the
dimethylsulfonamide 55 has very poor activity and selectivity in comparison
with the methylsulfonamide 54 (79 nM vs. 9 nM). The effect of incorporating a
methylene spacer between the aromatic ring and the polar group was also
investigated. With a 4-trifluoromethyl group on the phenoxy ring, the hydro-
xymethyl derivative 56 is reasonably potent (13 nM) but lacks selectivity,
particularly over DRI. Changing the benzyl alcohol to benzylamine 57 results
in a 4-fold drop in potency (59 nM), while converting the benzylamine to a
methylene spaced sulfonamide 58 has no effect on potency (55 nM) but results
in a loss of selectivity over NRI. With a 4-trifluoromethoxy group on the
phenoxy ring, however, the methylene-spaced sulfonamide 49 is potent (11 nM)
and retains excellent selectivity over DRI and NRI (4500-fold).
Based on the results above, the potent methylene-spaced sulfonamide 49
and N-linked sulfonamide 50 were investigated further to determine their
potential to be used as on-demand agents for PE. These compound both have
relatively low log D values of 2.1 and 2.3, respectively, but despite this still
show good flux in a Caco-2 assay with no eux (Figure 7.6). In vivo studies
showed that, in the dog, both compounds have a rapid T
max
(0.5 h) and low
volume of distribution (V
D
¼
6 and 4.5 L kg
1
, respectively, unbound V
D
¼
88
and 60 L kg
1
). In combination with moderate clearance (16 and 14mL
min
1
kg
1
, respectively), this resulted in half-lives of 4 h for both com-
pounds. The human PK for compound 50 was projected as possessing a T
max
of
0.5 h and a half-life of about 5 h (based on predicted clearance of 5mL
min
1
kg
1
and V
D
of 2 L kg
1
). The human oral bioavailability was also
predicted to be
75%.
Unfortunately, drug metabolism studies showed that these compounds are
largely metabolised to the monomethylamines 59 and 60. Monomethylamine
B
NMe
2
NMe
2
HLM T
1/2
>120 min
RLM T
1/2
>120 min
DLM T
1/2
>120 min
HLM T
1/2
>120 min
RLM T
1/2
>120 min
DLM T
1/2
>120 min
H
MeSO
2
N
H
MeSO
2
Caco 2 flux (AB/BA) 23/31
O
O
Caco 2 flux (AB/BA) 27/31
Dog PK
V
D
= 6 L/kg (unbound V
D
88 L/kg)
Cl = 16 mL/min/kg
T
1/2
= 4 h
T
max
= 0.5 h
Dog PK
V
D
= 4.5 L/kg (unbound V
D
60 L/kg)
Cl = 14 mL/min/kg
T
1/2
= 4 h
T
max
= 0.5 h
49
50
OCF
3
CF
3
Figure 7.6
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