Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Several highly selective COX inhibitors

    2020-11-23

    Several highly selective COX-2 inhibitors (coxibs) have been reported and marketed [6], including celecoxib [7] and etoricoxib [8] (Fig. 1). Even though these drugs produce less ulceration than conventional NSAIDs, coxibs still produce significant gastric and cardiovascular side effects due to the decrease in the protective prostacyclin (PGI2) production [9,10]. Therefore, there is an ongoing need for the discovery of new generations of selective COX-2 inhibitors with an improved gastric safety profile and minimal side effects. Luong et al. designed and synthesized derivative I (Fig. 2) by replacing carboxylic group present in zomepirac (non-selective NSAID) with the pyridazinone moiety. This modification highly improved the selectivity ratio of more than 1500 in favor of COX-2 enzyme [11,12]. Literature successfully used non-classic isosteres of the sulfonyl aryl group, such as pyridazinone (RS-57067 and Syntex compound) (Fig. 3) to make potent COX-2 inhibitors [13,14]. In addition, the presence of heterocyclic ring at position-6 of the pyridazinone ring has been reported to improve the anti-inflammatory activity with nil or very low ulcerogenicity, including for example, compounds II and III (Fig. 3) [15,16]. Furthermore, pyridazinone having an aryl group linked to position-6 through an ethenyl spacer is reported as a promising scaffold for the synthesis of COX-2 selective inhibitors. Some of these compounds are substituted at the amidic pyridazinone N (2), such as for example, glycogen synthase kinase 3 IV (Fig. 3) [17]. Inspired by all these findings and in the same direction, we have constructed pyridazinone A and B scaffolds as promising candidates for selective COX-2 inhibition (Fig. 3). Our strategy aims to designing a variety of modifications in the pyridazinone core, targeting exploring the impact of such on the desired selectivity, ulcerogenicity and anti-inflammatory activity and hoping to identify efficient COX-2 inhibitor, potent and safe anti-inflammatory lead. In our design strategy, we have utilized either the 4,5-dihydropyridazinone or pyridazinone core connected at position-6 with m-tolyl, o-methoxyphenyl or pyridyl moiety via an ethenyl spacer. We aimed to keep the amidic pyridazinone N (2) non-substituted or to incorporate a phenyl or 4-fluorophenyl group to the same. These synthesized compounds were initially tested for their in vitro COX-2 and COX-1 inhibition followed by the in vivo anti-inflammatory activity and the gastric ulcerogenic effect for the pyridazinones with the highest selectivity on COX-2 isoform.
    Results and discussions
    Conclusion The present study describes the synthesis of a series of pyridazinone derivatives 2a-f and 3a-e linked at postion-6 to an aryl or pyridyl moiety, through two carbons spacer. The synthesized compounds were evaluated as COX-2 inhibiting anti-inflammatory drug candidates, using indomethacin and celecoxib, as reference drugs. All the synthesized pyridazinones were highly potent COX-2 inhibitors, having IC50 values in nano-molar range. Moreover, they showed clear preferential COX-2 over COX-1 inhibition. Compounds 2d, 2f, 3c and 3d were of particular interest, as they exhibited the most prominent COX-2 inhibitory activity (IC50 values: 15.56–19.77 nM). They showed SIs of 24, 38, 35 and 24, respectively, which were 1.4–2.2 fold higher than celecoxib (SI 17). These four compounds were further investigated in vivo for anti-inflammatory activity and ulcerogenic liability. Compounds 2f, 3c and 3d demonstrated superior anti-inflammatory activity, relative to both indomethacin and celecoxib. None of these compounds showed gastric ulcerogenic effect. Compound 2d was equipotent to celecoxib at the second hour of oral administration, while at the fourth hour, it exhibited more potent anti-inflammatory activity than celecoxib, becoming equipotent to indomethacin. It showed mild hyperemia in vivo, compared to indomethacin and celecoxib. Compounds 2d, glycogen synthase kinase 3 2f, 3c and 3d were docked into the binding site pocket of COX-2 and showed perfect fitting within the pocket, with substantial interactions with the key amino acid residues His 90 and Arg 513. Accordingly, these active compounds represent promising leads to pursue as potential COX-2 inhibitors, to be used as potent and safe anti-inflammatory agents.