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  • We next turned our attention to the position


    We next turned our attention to the 6-position of the indole (). It was found that the chlorine atom present in was extremely important. The des-chloro analogue showed nearly 30-fold less affinity for the EP receptor in the binding assay and was nearly 30-fold lower in activity in the functional assay (FLIPR p 7.9±0.6). The fluoro analogue () was approximately 10-fold less active than chloro derivative , however, the bromo (, FLIPR p 9.7±0.3), trifluoromethyl (, FLIPR p 10.2±0.3), and methyl () analogues were of similar activity to the parent , in terms of binding affinity (). As the compounds in had shown they were amenable to alternative heterocyclic acids we next investigated this region of the molecule, namely the 1-position of the indole (). The thiazole could be replaced by the analogous oxazole (, FLIPR p 9.0±0.5) with minimal change in activity. The regioisomeric thiazole () was considerably weaker. Other 5-membered aromatic heterocycles with a heteroatom between the bcl-2 the indole, such as furan and thiophene displayed activity intermediate between and . A methylene linker could be inserted between the acid and thiazole (), or, more favorably, between indole and thiazole (). As we had found disparate SAR between compounds and , we were intrigued to see if the picolinic acid moiety would be tolerated in the 1-position of the indole template. Surprisingly, picolinate derivative was active, albeit with 10-fold lower activity than the parent thiazole . This result can be rationalized as an isobutyl group is preferred to benzyl in the 3-position of the indole (compare compound with ). In the parent thiazole series, both isobutyl and benzyl groups provided equal affinity (compare to and ). However, in the parent picolinate series, the isobutyl group was preferred over benzyl (compare to ), thus the fact that compound was essentially inactive could be attributed to the benzyloxy group and thus the corresponding isobutoxy analogue may show activity. Interestingly, the phenyl analogue showed extremely weak activity, highlighting the importance of a heteroatom to the carboxylic acid. The corresponding -benzoic acid derivative was essentially inactive, as was the acetic acid derivative . Finally, we investigated further substitution around the indole ring. Moving the Cl atom from the 6-position () to the 5-position () led to a 100-fold decrease in affinity (). This result, in conjunction with the activity of the des-chloro analogue () highlights the importance of a small lipophilic group in 6-position. Finally, addition of a methyl group to the 2-position of the indole also resulted in approximately 100-fold decrease in activity. The presence of the 2-methyl group may force the 3-isobutyl group into an unfavorable conformation for receptor binding. Taken together these results show low tolerance for the substitution of the indole ring (see ). Several compounds were profiled in vitro to assess their metabolic stability. Data for key compounds is shown () and is representative of the series. Based on a combination of in vitro metabolic stability and structural similarity to compounds which had previously shown good in vivo efficacy, compound was profiled in the CFA model of hypersensitivity,, data is depicted in . Compound demonstrated a good dose–response relationship with a calculated ED of 2.17mg/kg and efficacy equivalent to celecoxib at doses of 3 and 10mg/kg (po). Bioanalysis of samples from this study revealed a dose-proportional increase in blood exposure, blood concentrations were 0.44, 1.23, and 6.04μM at doses of 1, 3, and 10mg/kg, respectively. Further analysis from this study (top dose only) showed low levels of the compound in the brain, Br:Bl 0.05. This data highlights as a novel EP receptor antagonist with excellent in vivo efficacy. Compounds were synthesized according to the literature procedures or as outlined in , , , , , , . Full experimental details and characterizing data for key compounds has been described.