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  • In summary we have successfully identified

    2021-11-30

    In summary, we have successfully identified a series of potent and selective GSNOR inhibitors having imidazole and tetrazole functional groups in both end of the core structure and many compounds have been identified with IC: <25 nM and the best two compounds and in this series were having IC: <10 nM potency. Most of the selected GSNOR inhibitors were metabolically stable across species (human, rat and mouse) and majority of them had few CYP isoform liabilities (2D6, 2C9 and 2C19). Selected lead compound demonstrated favorable properties, low hERG activity, minimal off-target (POR) activity and reasonable oral pharmacokinetics (PK) including moderate oral bioavailability. Further, compound demonstrated ability to attenuate pulmonary inflammation ( efficacy), which supports the therapeutic potential of GSNOR inhibitor for the treatment of COPD. Since most of the disclosed GSNOR inhibitors has CYP liability, further SAR optimization of this series to afford minimal CYP liable compounds along with intranasal PK and efficacy study (inhalation route) will be the subject of Ion Channel Compound Library future publication. Acknowledgements We would like to thank Dr. Sanjib Das for the review of this manuscript, and Mr. Dayanidhi Behera for in vitro metabolic stability, CYP inhibition data to few selected compounds, and scientists from the analytical support group for their help in compound characterization. We also thank Dr. Pravin S Iyer for his support and encouragement.
    Introduction Peppers (Capsicum annuum L.), tomatoes and potatoes, belonging to the Solanaceae family, are of great agronomic and economic interest worldwide. Bell/sweet pepper fruits can be classified into three main types according to shape: California, Lamuyo and Dulce italiano. The California type is characterized by cube-shaped fruits of similar size along the transverse and longitudinal axes [1], [2], [3]. With regard to their culinary and nutritional values, pepper fruits have high levels of antioxidants, such as ascorbic Ion Channel Compound Library (vitamin C), carotenoids, including β-carotene (pro-vitamin A), and phenolic compounds [4], [5], [6], [7], [8]. Fruit ripening is a complex and irreversible process involving many changes at the phenotypic, structural and biochemical level [9], [10]. In the case of pepper, fruits undergo multiple biochemical and cellular modifications which involve variations in antioxidant content and increased carotenoid synthesis [11], [12], [13], loss of cellular integrity, changes in β-galactosidase and peroxidase activity [14], [15], carbon dioxide concentration [16] and increased NADPH content in mature fruits [1]. Nitric oxide (NO) is a radical molecule either directly or indirectly involved in many aspects of plant physiology under natural and environmental adverse conditions [17]. Thus, NO participates in reduction-oxidation processes which can affect signal transduction pathways, in which a family of NO-derived molecules, called reactive nitrogen species (RNS), plays a significant role. In many cases, this regulation process occurs through post-translational modifications (PTMs) of proteins, mainly nitration and/or S-nitrosylation (better known as S-nitrosation) [18], [19], [20]. The involvement of NO as a potential regulator of fruit ripening has been reported in different species such as strawberry [21], banana [22] and olive [23]. Although pepper fruits have a very active oxidative metabolism [2], [7], it has recently been demonstrated that NO metabolism could play an important role during the ripening process in this crop species. Specifically, protein nitration content has been shown to increase throughout this physiological process, with the antioxidant enzyme catalase being a prominent target which is negatively modulated by this posttranslational modification [3]. Given that S-nitrosothiols (SNOs) are important mediators of NO signaling, the main goal of this study was to analyze the activity, protein and gene expression of the S-nitrosoglutathione (GSNO) reductase, an enzyme directly involved in SNO regulation. Additionally, we studied the content of total S-nitrosylated (S-nitrosated) proteins with the aid of diaminofluorescein (DAF) gels. The data show that, during sweet pepper ripening, GSNOR activity is down-regulated, with a consequent increase in S-nitrosylated proteins, suggesting that NO metabolism plays a crucial role in this process.