Biocatalyzed Synthesis of Antidiabetic Drugs
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Glitazones, PPAR-γ agonists, are one of the earlier drugs used for treatment of T2DM (Nanjan et al., 2018). Ciglitazone (2a, Fig. 11.11) was discovered by Takeda in 1982, but rapidly discontinued (Gale, 2001). Troglitazone 2b was approved by FDA for T2DM in 1997, but after 6 weeks of its launch by Glaxo Welcome was withdrawn due to hepatotoxicity, and finally retired in 2000 (Nanjan et al., 2018). There are three marketed TZDs: pioglitazone (2c, Actos™ or Glustin™, Takeda Pharma USA and Eli Lilly), rosiglitazone (2d, Avandia™, GlaxoSmithKline), and lobeglitazone (2e, Duvie™, Chong Kun Dang), whose chemical structures are shown in Fig. 11.11. There are concerns about cardiovascular risks associated to rosiglitazone 2d, so that FDA placed some restrictions on it use, while EMA (European Medicine Agency) recommended its suspension from the market (Nanjan et al., 2018). On the other hand, the risk of developing bladder cancer associated to the use of pioglitazone 2c has been also reported (Shukla and Kalra, 2011). Lobeglitazone 2e was approved by the Ministry of Food and Drug Safety of Korea in 2013 (Lee et al., 2015), although the postmarketing surveillance is planned to finish in 2019. Chemical structure of glitazones.
Recent Developments in Therapies and Strategies Against COVID-19
Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga in The Covid-19 Pandemic, 2023
The thiazolidinediones are known as glitazones after ciglitazone, the prototypical drug of this class. These are heterocyclic compounds with a five-membered C3NS ring. The group was introduced in the late 1990s and is used in the treatment of diabetes mellitus type 2. Thiazolidinedione has shown efficiency against pulmonary disease induced by respiratory syncytial virus (RSV) or H1N1 influenza infection; however, their role in COVID-19 treatment is still not explored [72]. Thiazolidinediones upregulate ACE2 receptor, which is a binding target for COVID-19 virus in host cells. More studies and clinical trials are needed to establish any efficacy of this group against COVID-19 disease.
Introduction to Human Cytochrome P450 Superfamily
Shufeng Zhou in Cytochrome P450 2D6, 2018
Using a human fetal mRNA multiple-tissue cDNA panel lacking gastrointestinal tissues, a transient CYP2W1 mRNA expression in lungs, liver, skeletal muscle, and kidney at gestational week 30 is observed (Choudhary et al. 2005). Another study has observed the expression of CYP2W1 in the colon and small intestine at early stages of embryonic life but is completely silenced shortly after the birth (Choong et al. 2015). Immunohistochemical analysis of human fetal colon reveals that CYP2W1 expression is restricted to the crypt cells. The silencing of CYP2W1 after birth correlates with the increased methylation of CpG-rich regions in both murine and human CYP2W1 genes. In colorectal tumors, higher expression of CYP2W1 is associated with increased demethylation of the CpG island in the exon 1/intron 1 junction (Gomez et al. 2007). This implies interesting parallels between the developmental and cancer regulatory mechanisms of CYP2W1 expression. CYP2W1 and 2S1 are selectively induced in breast cancer cells only after treatment with 5F-203 (an AhR agonist, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole) or GW-610 (2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole), two new anticancer agents (Tan et al. 2011). CYP2W1 is important for the bioactivation of GW-610 in colorectal cancer cells, while CYP2S1 appears to be involved in the deactivation of benzothiazoles. CYP2W1 is also induced by imatinib (a BCR-Abl inhibitor used in the treatment of Philadelphia chromosome–positive [Ph+] chronic myelogenous leukemia), linoleic acid, and its derivatives in colon adenocarcinoma HCC2998 cells (Choong et al. 2015). The imatinib-mediated induction of CYP2W1 suggests an adjuvant therapy to treatment with duocarmycins that thus would involve induction of tumor CYP2W1 levels followed by the 2W1-activated duocarmycin prodrugs. However, CYP2W1 is not induced by the CAR agonist CITCO (6-(4-chlorophenyl)imidazo[2,1-b] [1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime) and the PPARγ agonist ciglitazone and TCDD, a potent AhR ligand (Choong et al. 2015).
Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential anti-diabetes agents: patent review (2015-2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Hidayat Hussain, Ivan R Green, Ghulam Abbas, Sergazy M Adekenov, Wahid Hussain, Iftikhar Ali
Tetrazole scaffold chemistry has a wide range of applications for medicinal chemistry and in the agriculture fields. These scaffolds have been widely used in pharmaceuticals in the form of carboxylic acid surrogates and lipophilic spacers. Literature surveys showed that tetrazole analogs often possess a wide range of biolgical properties viz., antidiabetic, antimicrobial, anticancer, anti-inflammatory, analgesic, antitubercular, and antihyperlipidimic effects [63]. Interestingly, there are a number of drugs having the tetrazole group that have been approved by the FDA for various diseases [63,64]. Moreover, 5-membered heterocycles have a long history in producing antidiabetic compounds viz, thiazolidinedione analogs such as ciglitazone, pioglitazone, AD-5061, and AD-5075 have demonstrated very potent in vitro and in vivo antidiabetic and related effects. Moreover Wy-49,322 was the first hypoglycemic agent which has the trazole ring [65].
Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future
Published in Critical Reviews in Toxicology, 2018
Melissa A. Davidson, Donald R. Mattison, Laurent Azoulay, Daniel Krewski
A class of TZDs was first discovered in the 1970s but it was not until the mid-1990s, after the early development of the fibrate drugs (agonists of the α PPAR subtype) and after TZD drugs such as ciglitazone, pioglitazone, and troglitazone had begun clinical development, that it was discovered that TZDs exerted insulin-sensitizing effects through direct activation of PPARs, specifically the γ subtype (Colca et al. 2014b). Since that time, it has been discovered that dependent upon cell type or binding site, TZDs act as synthetic agonists or antagonists of PPARs, a subfamily of nuclear receptors comprised of α, β/δ, and γ isoforms (Lehmann et al. 1995; Nuclear Receptors Nomenclature Committee 1999). Like other nuclear receptors, PPARs are comprised of distinct functional domains which are potential targets for modulation of signaling cascades (Ahmadian et al. 2013), including a ligand-binding domain (Moras and Gronemeyer 1998), a highly conserved DNA-binding domain (Poulsen et al. 2012), and a transactivation domain that allows for ligand-independent activation (Werman et al. 1997). After ligand binding, PPARs undergo specific conformational changes that allow for the differential recruitment of protein coactivators (Willson et al. 2001). As ligands differ in their ability to interact with coactivators, they can induce a number of diverse biologic and metabolic responses (Poulsen et al. 2012; Ahmadian et al. 2013).
PPARγ induces PD-L1 expression in MSS+ colorectal cancer cells
Published in OncoImmunology, 2021
Tobias Gutting, Veronika Hauber, Jens Pahl, Kay Klapproth, Wenyue Wu, Ioana Dobrota, Frank Herweck, Juliane Reichling, Laura Helm, Torsten Schroeder, Beifang Li, Philip Weidner, Tianzuo Zhan, Maximilian Eckardt, Johannes Betge, Sebastian Belle, Carsten Sticht, Timo Gaiser, Michael Boutros, Matthias P.A. Ebert, Adelheid Cerwenka, Elke Burgermeister
In NK cells, PPARs confer lipotoxicity to limit antitumor responses in vivo.25 Obesity evokes lipid accumulation causing ”paralysis” of NK cell functions. Herein, PPARα/δ agonists and natural fatty acids mimic obesity, inhibit glycolysis and abolish delivery of cytotoxic factors from the NK/tumor cell synapse. Natural (15d-PGJ2) and synthetic (ciglitazone) PPARγ-agonists compromise IFNγ synthesis and cytotoxic activity of human/murine NK cells.47 Thus, metabolic reprogramming of innate and adaptive immune cells in the systemic or local tumor microenvironments via pharmacological targetable nuclear receptors of the PPAR/PGC1 families may be exploited to improve the efficacy of current clinically-in-use checkpoint Ab therapies.
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