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    • br The synthesis of these antagonists

    2019-07-02


    The synthesis of these antagonists relied heavily on Stille and Suzuki coupling reactions. The preparation of the required building blocks is presented in . Reduction of ethyl 6-bromo-2-pyridinecarboxylate with diisobutylaluminum hydride in tetrahydrofuran followed by treatment with triisopropylsilyl trifluoromethanesulfonate afforded silyl ether in 98% yield. Benzyl ether was obtained quantitatively by treatment of 2-bromo-4-chlorophenol with benzyl bromide. Subsequent addition of -butyllithium followed by triisopropyl borate afforded boronic troglitazone in 73% yield. Palladium-catalyzed stannylation of ethyl 5-bromonicotinate resulted in the quantitative production of arylstannane . The elaboration of the tricyclic 2,3-diarylthiophenes is shown in . First, Suzuki coupling between the appropriate aryl bromides – and 3-thiopheneboronic acid afforded the corresponding 3-arylthiophenes –, which upon treatment with -bromosuccinimide, yielded the 2-bromo-3-arylthiophenes –. Further Suzuki coupling reactions between intermediates and with boronic acid afforded 2,3-diarylthiophenes and . Alternatively, Stille coupling between bromothiophene and 3-pyridylstannane gave access to analog . The final transformations leading to antagonists and are shown in . Deprotection of silyl ether with tetrabutylammonium fluoride (TBAF) followed by oxidation of the resulting primary alcohol with potassium permanganate afforded antagonist in 62% yield. Reduction of nicotinate derivative with sodium borohydride followed by oxidation with manganese oxide afforded the corresponding aldehyde. Reaction of this intermediate with (trifluoromethyl)trimethylsilane and TBAF followed by a further oxidative treatment with manganese oxide gave access to trifluoromethylketone hydrate . In conclusion, we have optimized a novel series of potent EP receptor antagonists. The results of the SAR study in this series led to the identification of antagonists , , and , which exhibit high affinity for the human EP receptor (<10nM) and a selectivity greater than 100-fold against the EP, EP, EP, DP, FP, and IP receptors and greater than 25-fold versus the TP receptor. These three antagonists present good pharmacokinetics in rats. Interestingly, antagonists , , and show significant differences in the way they are distributed in rats with brain to blood ratios of 0.1, 1, and 7, respectively. The overall profiles of these antagonists are complementary and appropriate for the pharmacological evaluation of EP antagonism. These results will be reported in due course.
    Introduction PGE2 is a major mediator present at sites of inflammation [1]. It is well established that PGE2 contributes to the localized and systemic symptoms of inflammation. A key study by Portanova et al. [2] demonstrated that anti-PGE2 antibodies were able to reverse the swelling and pain in localized inflammation. This directly connects PGE2 to the development of inflammatory symptoms. The major pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), which are produced in response to inflammatory stimuli such as lipopolysaccharide, sequentially induce PGE2 biosynthesis from macrophages in a concentration-dependent manner [3]. However, other early studies also showed that exogenous PGE2 potently suppressed the production of TNF-α from monocytic cells (at the transcriptional level) and the suppression of endogenous PGE2 production (using cyclooxygenase inhibitors) enhanced TNF-α synthesis clearly indicated that the downstream release of PGE2 is a negative-feedback loop [4,5]. It is now recognised that prostaglandins in general, and PGE2 in particular, play a cytoprotective and controlling role in limiting immune and inflammatory activation and consequent pathology [6]. Thus, the suppressive action of PGE2 on TNF-α production is an important axis in limiting the extent of an inflammatory response. The actions of PGE2 are mediated via at least 4 membrane receptors termed EP1–EP4, each with its particular signalling system some of which overlap [6]. Suppression of TNF-α production in monocytic cells can occur via EP2 receptors on the basis of a variety of agonists and antagonists of the respective receptors [1]. In the study of Brown et al. [1] it was also shown that the inhibition of TNF-α production by PGE2 could be reversed to an extent by an EP4 receptor antagonist. However, it is very clear that these compounds have greatly overlapping activities with relatively poor selectivity between EP receptor subtypes, particularly to distinguish clearly between EP2 and EP4 receptors. Thus, an alternative approach is required to attempt to delineate which precise EP receptors are involved in controlling monocyte-derived cytokine production, particularly TNF-α.