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The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the molecule and on the therapeutic class, but it also depends on the chemical reactivity of piperazine-based synthons, which facilitate its insertion into the molecule. In this paper, we take into consideration the piperazine-containing drugs approved by the Food and Drug Administration between January 2011 and June 2023, and the synthetic methodologies used to prepare the compounds in the discovery and process chemistry are reviewed. [ABSTRACT FROM AUTHOR]

Objective: This review aims to provide some theoretical guidance for the precise treatment of ovarian cancer and the development of estrogen-related drugs. Mechanism: Ovarian cancer is one of the leading causes of death in gynecological cancer patients, mainly affecting middle-aged and elderly women. It has the characteristics of hidden location, strong heterogeneity and lack of specific symptoms in the early stage. Numerous studies have shown that estrogen receptor (ER) plays an important role in different types of cancer, including ovarian cancer. Accordingly, the study of ER signaling pathways and related regulatory factors in ovarian cancer cells should help us understand the pathogenesis of ovarian cancer. Findings in Brief: The expression of estrogen receptor subtypes is related to ovarian cancer gene and leads to ovarian cancer. Estrogen receptor modulators appear to be an important factor in the prognosis of patients with ovarian cancer after hormone therapy. Conclusions: This review summarizes the regulatory mechanism of ER in the occurrence and development of ovarian cancer and outlines the specific role of estrogen receptor modulators (SERMs) in the treatment and prevention of ovarian cancer.

An unmet medical need exists for the development of targeted therapies for the treatment of inflammatory bowel disease (IBD) with easily administered and stable oral drugs, particularly as most patients on biologics [i.e., tumor necrosis factor (TNF) inhibitors and anti-integrins] are either primary non-responders or lose responsiveness during maintenance treatment. A new class of small molecules, sphingosine-1-phosphate (S1P) receptor modulators, has recently shown efficacy in IBD. Here we provide an overview of the mechanism of action of this novel treatment principle in the context of intestinal inflammation. The remarkable impact of therapeutic modulation of the S1P/S1P receptor axis reflects the complexity of the pathogenesis of IBD and the fact that S1P receptor modulation may be a logical therapeutic approach for the future management of IBD. [ABSTRACT FROM AUTHOR]

. Purpose: This study aims to investigate the effects of systemic application of sphingosine 1-phosphate receptor 1(S1P1) on allogeneic corneal transplantation in mice. Methods: A total of 112 BALB/c mice received corneal grafts from C57BL/6 donors. Recipients were randomly divided into seven groups and treated with intraperitoneal injections of S1P1 (5 mg/kg/days), cyclosporine A (5 mg/kg/days), dexamethasone (1 mg/kg/days) and rapamycin (2 mg/kg/days). S1P1was combined with rapamycin or cyclosporine A, and saline served as negative control. Serum levels of IL-2, IL-10, TGF- β1 and IFN-γ were measured by Elisa. The numbers of CD4+ T and regulatory (Treg) cell phenotype were measured by flow cytometry. Cytokine mRNA expression was analysed by real-time quantitative PCR. CD4+ T cells and cytokines were histologically identified by immunofluorescence staining. Results: Corneal graft survival was prolonged by intraperitoneal injections in S1P1 alone (mean survival time MST, 35.3 ± 5.6 days), S1P1 combined with rapamycin (MST, 38.7 ± 6.5 days) or S1P1 and cyclosporine A (MST, 32.7 ± 4.8 days) compared with the controls (MST, 14.6 ± 0.2 days; n = 5, p < 0.01). S1P1 alone increased CD4+ T (p < 0.01) and Treg cells (p < 0.01; n = 5) in the cervical and mesenteric lymph nodes compared with the controls and S1P1 + rapamycin (p < 0.05; n = 5). TGF- β1 and IL-10 mRNA transcriptions in corneal grafts following S1P1+ rapamycin increased (both p < 0.01; n = 3), and TGF- β1 and IL-10 in the serum level following S1P1 alone increased (both p < 0.01; n = 3). These results paralleled the findings obtained from immunofluorescence. Conclusion: S1P1 has significant effect in corneal allograft rejection inhibition. The combined treatment of S1P1 and rapamycin results in synergistic effect. [ABSTRACT FROM AUTHOR]

Introduction: Oxadiazole is a unique class of heterocycle, possessing numerous important biomedical and therapeutic applications, such as anti-bacterial, anti-cancer, anti-inflammatory, inhibitors for diverse enzymes, receptor modulators, and neuroprotective properties. The rapid development in the field of oxadiazole-containing structures is confirmed by the development of numerous clinical drugs, such as doxazosin, nesapidil, pleconaril, fasiplon, ataluren, zibotentan, and prenoxdiazine as selected examples., Areas Covered: This review provides a comprehensive overview of the range of biological applications of oxadiazole-containing drugs in a range of patents from 2013 to 2021. The information was collected from available data sources including SciFinder, Reaxys, MedLine, and Chemical Abstracts., Expert Opinion: Oxadiazole is an established class of compounds with fascinating biological properties. The importance of oxadiazoles can be recognized by their enormous application in a wide spectrum of medicinal chemistry from anticancer, lantibiotics, and antidiabetics to their use in agriculture and neuroprotection. For instance, the oxadiazole-based compounds have shown the ability to modulate a variety of receptors including the M4 receptor agonists, S1P1 receptor modulators, SSTR5 antagonists, orexin type-2 receptor agonists, liver X receptor agonists, and many more. This testifies to the special features associated with the oxadiazole scaffold, making it a significant pharmacophore.

Epidemiological data suggest that the steroid hormone 17β-estradiol plays an important role in protecting the brain from neurodegenerative processes, including that causing the loss of dopamine (DA) neurons in Parkinson’s disease. Determining the mechanisms of neuroprotection in experimental systems may facilitate the development of estrogenic therapies for these diseases. The present study sought to further investigate the mechanism of the neuroprotective effect of 17β-estradiol in a murine model of Parkinson’s disease, i.e. 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal DA depletion. Consistent with previous findings, 17β-estradiol was found to inhibit MPTP-induced DA depletion under a dosing regimen (repeated daily administration) that mimicked physiological levels of the steroid. However, high doses of the steroid administered repeatedly or acutely failed to inhibit toxicity, as did 17α- estradiol. These data suggest that the neuroprotective effect of 17β-estradiol was mediated through an interaction with one of the nuclear estrogen receptors, and is not the result of an antioxidant action. In order to realize the therapeutic potential of the neuroprotective effect of 17β-estradiol for Parkinson’s disease, it will be necessary to identify synthetic estrogen receptor modulators that lack the activity of the steroid on peripheral tissue. In this study, raloxifene failed to mimic the neuroprotective effect of 17β-estradiol against MPTP toxicity. Thus, exploration of new compounds with different pharmacological and/or physiochemical properties is warranted.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Adenosine is a ubiquitous signaling nucleoside molecule, released from different cells within the body to act on vasculature and immunoescape. The physiological action on the proliferation of tumour cell has been reported by the presence of high concentration of adenosine within the tumour microenvironment, which results in the progression of the tumour, even leading to metastases. The activity of adenosine exclusively depends upon the interaction with four subtypes of heterodimeric G-protein-coupled adenosine receptors (AR), A1, A2A, A2B, and A3-ARs on the cell surface. Research evidence supports that the activation of those receptors via specific agonist or antagonist can modulate the proliferation of tumour cells. The first category of AR, A1 is known to play an antitumour activity via tumour-associated microglial cells to prevent the development of glioblastomas. A2AAR are found in melanoma, lung, and breast cancer cells, where tumour proliferation is stimulated due to inhibition of the immune response via inhibition of natural killer cells cytotoxicity, T cell activity, and tumourspecific CD4+/CD8+ activity. Alternatively, A2BAR helps in the development of tumour upon activation via upregulation of angiogenin factor in the microvascular endothelial cells, inhibition of MAPK and ERK 1/2 phosphorylation activity. Lastly, A3AR is expressed in low levels in normal cells whereas the expression is upregulated in tumour cells, however, agonists to this receptor inhibit tumour proliferation through modulation of Wnt and NF-κB signaling pathways. Several researchers are in search for potential agents to modulate the overexpressed ARs to control cancer. Active components of A2AAR antagonists and A3AR agonists have already entered in Phase-I clinical research to prove their safety in human. This review focused on novel research targets towards the prevention of cancer progression through stimulation of the overexpressed ARs with the hope to protect lives and advance human health., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)