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  • The potential use of derivatives belonging to this series as

    2022-12-01

    The potential use of derivatives belonging to this series as therapeutic agents mostly depends on their pharmacokinetics and pharmacodynamics. The pharmacokinetic phase includes absorption, distribution, metabolism and excretion (ADME) of the studied compounds. Therefore, preliminary data for theoretical ADME profiles of the newly synthesized compounds were determined () with properties calculated using the methodology developed by Molinspiration property program. Log P, expressed as the octanol-water partition coefficient, was calculated as a sum of fragment-based contributions and correction factors. Molecular Volume (MV) and Topological Surface Area (TPSA) were calculated as a sum of fragment contributions, the latter following the methodology by Ertl et al. From the data obtained, it can be observed that no violation of Lipinski’s rule (molecular weight (MW) <500; Log P <5; number of H-bond donors (HBD) <5, and acceptors (HBA) <10) was found, making derivatives –, , , promising leads. Thus, one can notice that all the herein reported compounds possess log P values compatible with those required to cross membranes. Moreover, TPSA is also found to be as good for potential therapeutics and also MV values are in agreement.
    Introduction Myopia, especially high myopia, is a growing problem in many areas of the world (Bar Dayan et al., 2005; Holden et al., 2016; Lin et al., 2004; Vitale et al., 2008; Williams et al., 2015; Woo et al., 2004). Myopia is a risk factor for sight-threatening conditions such as glaucoma, retinal detachments, and macular choroidal neovascularization (Koh et al., 2016; Mitchell et al., 1999; Saw et al., 2005; Shen et al., 2016; Wong et al., 2014). Maculopathy secondary to high myopia is a leading cause of irreversible legal blindness in many Asian countries (Hsu et al., 2004; Iwase et al., 2006; Wong et al., 2014). In the United States alone, the annual direct cost of correcting distance vision is over $3.8 billion, and the total financial burden to the U.S. economy is over $35 billion yearly (Frick, 2012; Rein et al., 2006; Vitale et al., 2006). Thus strategies to prevent myopia or to slow its progression would be beneficial for both individual patients and national health care systems. Myopia is most commonly attributed to increased axial length of the eye. Axial growth ultimately occurs through tissue remodeling that increases the creep rate of the sclera, allowing the tough, fibrous WZ4003 to stretch and axially elongate the eye (Phillips et al., 2000; Siegwart and Norton, 1999). Myopic axial elongation results in a reduction in scleral collagen content and a decrease in collagen fibril diameter (McBrien et al., 2000). The discovery that 7-methylxanthine (7-MX), a metabolite of caffeine (1,3,7-trimethylxanthine), increased scleral collagen fibril diameter (Trier et al., 1999) suggested that methylxanthines could protect against myopia progression. Subsequently, 7-MX was shown to significantly reduce myopic progression in rabbits, guinea pigs, macaques, and children (Cui et al., 2011; Hung et al., 2018; Nie et al., 2012; Trier et al., 2008). Though the precise mechanism by which 7-MX alters scleral collagen and slows myopia progression is unknown, caffeine and its metabolites are known to block adenosine receptors non-selectively at low or physiological concentrations (10–50 μM) (Daly et al., 1983; Fredholm, 1985). At much higher concentrations, caffeine inhibits phosphodiesterases (100–10,000 μM) and activates ryanodine receptor channels (300–2000 μM) (Fredholm, 2011). Since it is debatable whether such high concentrations are physiologically relevant, adenosine receptor blockade is the most likely mechanism of action. Adenosine is a ubiquitous neuromodulator present in various forms in all cells of the body, and adenosine receptors (ADORs) are membrane-bound G-protein coupled receptors. Four adenosine receptors have been identified, A1, A2a, A2b, and A3, each of which is coupled to different constellations of G-proteins (Fredholm et al., 2001). As a general rule, ADORA1 and ADORA3 are coupled to Gi/o proteins to initiate inhibitory intracellular signaling, leading to decreases in intracellular cyclic adenosine monophosphate (cAMP) and inhibition of protein kinase A. ADORA2a and ADORA2b are coupled to Gs/olf to initiate excitatory or facilitative intracellular signaling (Alfinito et al., 2002; Epperson et al., 2009; Freund et al., 1994; Gao et al., 1999; Gerwins and Fredholm, 1995; Jockers et al., 1994; Kull et al., 2000; Olah, 1997; Oliveira and Correia-de-Sa, 2005; Palmer et al., 1995). ADORA1, ADORA2a, and ADORA3 are activated at physiologic concentrations of adenosine, but ADORA2b is only activated at higher concentrations, such as those resulting from inflammation, ischemia, or tissue damage (Fredholm, 2007). ADORs form homo- and hetero-dimers with other ADORs, P2 adenine receptors, dopamine receptors, and adrenergic receptors (Chandrasekera et al., 2013; Ciruela et al., 1995; Ferré et al., 1992; Fredholm et al., 2011; Ginés et al., 2000; Gracia et al., 2013; Komatsu et al., 2012; Orru et al., 2011; Sattin et al., 1975).