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    • Fig summarizes the underlying mechanism of SB

    2022-06-23

    Fig. 7 summarizes the underlying mechanism of SB on inhibiting inflammation and maintaining epithelium barrier integrity in the TNBS-induced colitis model. Our findings not only explained the protective effect of SB on colon health, but also provided evidence that GPR109A likely constitutes a valid therapeutic target in IBD. Inhibition of macrophages by activating GPR109A thus may represent a novel approach to treat IBD.
    Nicotinic mth1 inhibitor     (niacin) has been a leading treatment for dyslipidemia and for the prevention of atherosclerosis for over 40years. Long term clinical studies have demonstrated niacin’s ability to reduce the incidence of mortality from coronary heart disease. In spite of niacin’s clinical significance, patients treated with niacin show low compliance of use due to an intense flushing side effect. In response to the maladies of niacin therapy, a number of drug discovery programs have focused on the development of a ‘flush-free’ niacin-like therapy. Despite considerable effort in the field, the absence of a niacin-related target and/or mechanism of action, has limited such investigations. Recently, a high affinity G-protein coupled receptor, GPR109a, has been identified for niacin. Mechanistic studies have suggested that niacin may exert its therapeutic effect through the activation of GPR109a located on adipocytes. Experiments have shown that niacin activation of GPR109a results in a reduction of intracellular cAMP. It is believed that this down regulation of cAMP in adipocytes, triggers a cascade of events that results in the lipid altering affects associated with niacin treatment (i.e., raise in HDL, lower triglycerides and LDL). In control experiments, GPR109a receptor knockout mice, when treated with niacin therapy, failed to show the characteristic reduction in plasma FFA that is observed upon niacin treatment in wild type mice. Furthermore, niacin receptor knockout mice, when treated with niacin therapy, failed to show a niacin-induced flush. As a result, it is concluded that the niacin-associated flush and anti-lipolytic effects are both mediated through the niacin receptor. Following the identification of the high affinity niacin receptor (GPR109a), our group initiated a drug discovery program focused on the development of a ‘flush-free’ agonist. A high-throughput screen of our compound collection, followed by a hit to lead effort, identified anthranilic acid derivative as a promising lead structure. Despite an excellent in vitro profile, the modest ADME properties and the high serum-potency-shift (>10,000-fold) of compound highlighted the need for further structure based improvements. Our initial medchem effort focused on strategies to alleviate the large serum shift effect observed for the class. Previous work in the group revealed a tight binding environment around the anthranilic acid moiety and the terminal phenol group. With this in mind, our strategy involved the localization of an amino moiety on the carbon chain connecting the head-anthranilic acid group and the biphenyl tail region. As illustrated in , the incorporation of an amino group into the architecture of had a significant effect on the serum shift. Analysis of in our in vitro binding assay, in the presence of 4% human serum, revealed a 20-fold reduction in serum-potency-shift, when compared to the des-amino derivative . Based on this result, we were motivated to look at other members of this lead class. In this regard, introduction of the amino group into the high affinity thiazole derivative and the tricyclic-pyrazole derivative showed a similar 10-fold reduction in serum shift. However, despite the amino group’s favorable effect on serum shift, the reduced affinity for serum proteins was accompanied by a 10-fold loss in potency on the receptor. While this trend was consistent amongst most members of the class, oxadiazole was less affected by the change. In this case, amino-oxadiazole showed a characteristic 5-fold reduction in serum shift, relative to the parent, and comparable in vitro activity.