Chemistry Reference
In-Depth Information
A
B
Vehicle
10 mg/kg, Cmpd 6
35
30 mg/kg, Cmpd 6
20
10 min
30 min
60 min
100 mg/kg, Cmpd 6
30
*
*
*
*
*
**
15
25
**
**
*
**
10
*
20
***
***
**
5
15
0
10
0
30
60
90
120
Time (min)
Compound 6
Figure 13.4
(A) Pretreatment with cinnamide 6 dose-dependently inhibited capsaicin-
induced eye-wiping behavior in rats (i.p. administration). (B) Effect of 6
on CFA-induced thermal hyperalgesia in rats. Significant reversal of
CFA-induced thermal hyperalgesia was observed with 30 and 100mg
kg
1
(i.p.) doses of cinnamide 6. Reproduced with permission of the
American Society for Pharmacology and Experimental Therapeutics
from J. Pharmacol. Exp. Ther., 2005, 313, 474.
high first-pass metabolism and poor oral absorption in rats. Therefore, we
undertook an extensive SAR investigation to improve both the potency and
pharmacokinetic properties of compound 6. Early metabolism identification
studies showed that the para tert-butyl group was extensively oxidized in
human liver microsomes (HLM Cl
in vitro
¼
574 mLmin
1
mg
1
).
50
In this pre-
liminary study we found that a trifluoromethyl group could replace the para
tert-butyl group and served to give a compound with increased metabolic
stability (HLM Cl
in vitro
¼
72 mLmin
1
mg
1
). In addition, we found that the 7-
quinolinyl group was an acceptable substitution for the benzodioxan-7-yl
moiety and gave analogues with increased TRPV1 potency (e.g., compound 7;
Figure 13.5). Unfortunately, cinnamide 7 still suffered from poor oral bio-
availability in rats (F
oral
¼
5%).
To further advance our understanding of this series, we also conducted a
conformational analysis of several N-arylcinnamides to gain insights into the
optimum orientation of the pharmacophoric elements required for TRPV1
inhibitory activity.
51,52
In these studies, we examined the conformational pre-
ferences of several N-arylcinnamides using Monte Carlo searching and ab initio
quantum mechanical calculations at the 6-31G* level.
53
We found that the s-cis
conformation of compound 6 was preferred over the s-trans conformation by
2.6 kcal mol
1
and that analogues that were better able to adopt the s-cis
conformation were more potent TRPV1 antagonists (Figure 13.6). Based on
this conformational analysis, we proposed that the bioactive conformer of the
N-arylcinnamide 6 was s-cis, with a coplanar arrangement of the amide car-
bonyl, the cinnamide double bond, and the b-substituted aryl group being
optimal.
Search WWH ::
Custom Search