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  • Although MMP might be a

    2019-07-10

    Although MMP-9 might be a downstream target of Src kinase signaling (Liu and Sharp, 2011), a direct connection has not been established. We showed for the first time that, in the collagenase-induced ICH model, Src kinase signaling regulates MMP-9 activity and mediates EP1R toxicity. Consistent with these findings, we and others have shown that MMP-9 inhibition or rna polymerase is neuroprotective after ICH (Wang and Tsirka, 2005a, Xue et al., 2009a, Xue et al., 2009b). The molecular mechanism by which Src kinase signaling regulates MMP-9 activity after ICH remains to be defined. Our study provides proof of concept that EP1R inhibition has neuroprotective effects with clinical implications for patients with ICH. However, we need to establish whether EP1R inhibition is also effective in higher species, such as piglets and monkeys, and whether sex differences affect the ICH outcomes conferred by EP1R inhibition. Furthermore, PGE2 acts through receptors EP1–4, and the synergistic or antagonistic effects of EP1R with other EP receptors must be defined. Although we have tested SC51089 in our in vivo and in vitro ICH models, more selective EP1R antagonists are available (Jones et al., 2009), and their neuroprotective potency needs to be systematically evaluated. In summary, we provide the first preclinical evidence that PGE2 EP1R plays a toxic role after ICH through mechanisms that involve the Src kinases and the MMP-9 signaling pathway. Hence, EP1R inhibition could be developed as a novel therapeutic strategy to reduce inflammatory injury and improve functional outcomes after ICH.
    Conflicts of interest
    Acknowledgments
    Scaffold hopping involves transforming one pharmacophoric template into another. The rationale behind this type of transformation is that the new template will carry some form of benefit or distinguishing factors over the starting template, for example, improved potency, different selectivity, or improved pharmacokinetics. We have described several series of EP receptor antagonists, , as potential analgesics. Compounds from these several series have shown efficacy in the Complete Freund’s Adjuvant model of inflammatory pain., As part of an ongoing medicinal chemistry programme we were interested in identifying further novel EP receptor antagonists and profiling their potential for the treatment of inflammatory pain. One series of EP receptor antagonists we have reported is exemplified by the pyrazole derivative . We have also disclosed some related work from this series where we identified replacement heterocycles for the pyrazole, such as the thiazole derivatives and and the pyridine derivatives and . We found that the central methylene linker could be replaced by an amino linker when the heterocycle on the right-hand side was thiazole but not pyridine, compare compounds and , . We were fascinated by this disparity in SAR and intrigued by the potential intramolecular bond that could be formed between the -alkoxy group and the biaryl NH of generic structure , . We hypothesized that an intramolecular hydrogen bond could occur and that this could be mimicked by indoles such as (). However, we were uncertain if the indole would provide the bioactive conformation as the methylene-linked compounds were active and modeling suggested that in the lowest energy conformation thiazole derivative resided in a non-planar conformation (). In order to test this hypothesis we synthesized compounds of general structure (, R=Bn or -Bu). Compounds were tested in [H]-PGE binding assay. Selected compounds were also tested in a functional Ca mobilization assay (FLIPR). The first compound prepared was and we were pleased to find that it was a potent EP receptor antagonist with a binding pIC of 8.2 (IC 6.3nM). Furthermore, showed potent activity as a functional EP antagonist with a p of 9.3±0.3 ( 0.5nM) in a functional assay (FLIPR) (). Based on this result we went on to explore initial SAR in the 3-position of the indole and investigated some alkyl groups which would mimic preferred groups from the corresponding alkoxy series, . Thus, we prepared benzyl derivative which was surprisingly found to be 30-fold lower in affinity than in the binding assay, and 100-fold weaker in the FLIPR assay (p 7.2±0.4). Several alternative alkyl groups were investigated, –. The SAR shows that large groups such as CHCH-Bu () (FLIPR p 8.4±0.8) are best. Complete removal of the 3-substituent () led to erosion of activity. A ketone was tolerated () in terms of functionality, but the corresponding amide () was considerably less active. Placement of basic functionality ( and ) severely diminished affinity. Taken together these results imply the group in the 3-position of the indole forms a lipophilic interaction with the receptor which is in accordance with our hypothesis of the receptor binding interaction for compounds such as .