S. H. Watterson et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7006–7012
7011
Table 6
Tissue disposition of 4ma in SDb rat and SJLc mice
Tissue
Rat AUC8h
(l
M⁄hr)
Mouse AUC8h (l
M⁄hr)
Dose (iv)
Plasma
Liver
2 mg/kg
13
16
8 mg/kg
18
81
Intestines
156
1,170
a
b
c
Vehicle: 0.02 N HCl (aq).
Sprague Dawley rats.
SJL mice.
Figure 5. Histopathological evaluation of 4m (3 and 10 mg/kg) versus dexa-
methasone (Dex) in mouse TNBS-induced IBD (p <0.05 vs. vehicle at 10 mg/kg).
along with its impressive efficacy in the rat adjuvant-induced
arthritis study, suggested that 4m would be effective in the treat-
ment of inflammatory bowel disease (IBD). In order to evaluate its
efficacy, 4m was profiled in the murine 2,4,6-trinitrobenzene sul-
fonic acid (TNBS)-induced colitis model at doses of 3 and 10 mg/
kg (BID) for 4 days beginning with dosing on day 1, before the TNBS
challenge. Body weights were measured daily, and the colons were
collected on day 4 to determine terminal colon length. Analogue
4m demonstrated clear dose dependent efficacy with the
10 mg/kg dose group maintaining body weight (Fig. 3) and colon
length (Fig. 4) similar to that of the dexamethasone control group
and healthy mice. The 3 mg/kg group, on the other hand, did not
offer any benefit over the vehicle group with mice showing
10–15% loss in body weight and an approximately 1 cm loss in
colon length. Additionally, histopathological evaluation (Fig. 5)
revealed that the 10 mg/kg BID dose had resulted in significant
reduction in both inflammation and tissue damage relative to the
vehicle group.9 These results suggest that 4m may be effective in
treating IBD in humans.10
In summary, SAR investigation into replacing the ‘azaindole’ C-2
phenyl substituent with a pyridine ring resulted in improved
in vitro potency, physicochemical properties, and pharmacokinetic
parameters. Based on its in vitro potency, selectivity, favorable lia-
bility profile, impressive efficacy in arthritis models, and signifi-
cant distribution to the GI tract, analogue 4m was chosen for
evaluation in a murine TNBS-induced colitis model where it dem-
onstrated impressive efficacy when dosed at 10 mg/kg BID. Further
studies on the evaluation of this compound as well as further ‘aza-
indole’ chemotype optimization will be reported in due course.
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Figure 3. Body weight changes for 4m (BID dosing) compared with vehicle and
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Figure 4. Terminal colon lengths for 4m compared with vehicle and dexametha-
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