Synthetic pancreatic lipase inhibitors: Difference between revisions
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=== Fluoroquinolones and triazolofluoroquinolone === |
=== Fluoroquinolones and triazolofluoroquinolone === |
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Scaffold similarities in the structures of reported pancreatic lipase inhibitors based on isoquinoline and quinolone structures were the basis to investigate the anti-pancreatic lipase activities of the synthetic fluoroquinolones (FQs). In effect, FQs, mostly known as potent and effective antibacterials and recently have been proven to act as potential pancreatic lipase inhibitors. Triazolofluoroquinolones (TFQs) exhibit PL inhibitory activity with appreciable anticancer propensities. Twelve newly synthesized FQs and TFQs were tested with respect to their in vitro antilipase and antiproliferative activities and were evaluated for their antilipolytic efficacy and potency properties. . The PL-IC50 values ( concentration that reduces the effect by 50% ) of 12 FQs and TFQs were in the range of 12.5–189.1 μm. . The IC50 value of the reference compound, orlistat, was 0.2 μm. Table 1 reveals that FQs 4a, 4c, 3b, and 5b exhibited significant inhibitory activity with PL-IC50 values.<ref>{{cite journal | |
Scaffold similarities in the structures of reported pancreatic lipase inhibitors based on isoquinoline and quinolone structures were the basis to investigate the anti-pancreatic lipase activities of the synthetic fluoroquinolones (FQs). In effect, FQs, mostly known as potent and effective antibacterials and recently have been proven to act as potential pancreatic lipase inhibitors. Triazolofluoroquinolones (TFQs) exhibit PL inhibitory activity with appreciable anticancer propensities. Twelve newly synthesized FQs and TFQs were tested with respect to their in vitro antilipase and antiproliferative activities and were evaluated for their antilipolytic efficacy and potency properties. . The PL-IC50 values ( concentration that reduces the effect by 50% ) of 12 FQs and TFQs were in the range of 12.5–189.1 μm. . The IC50 value of the reference compound, orlistat, was 0.2 μm. Table 1 reveals that FQs 4a, 4c, 3b, and 5b exhibited significant inhibitory activity with PL-IC50 values.<ref>{{cite journal |last1=Arabiyat |first1=Shereen |last2=Kasabri |first2=Violet |last3=Al-Hiari |first3=Yusuf |last4=Bustanji |first4=Yasser K. |last5=Albashiti |first5=Rabab |last6=Almasri |first6=Ihab M. |last7=Sabbah |first7=Dima A. |title=Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones |journal=Chemical Biology & Drug Design |date=December 2017 |volume=90 |issue=6 |pages=1282–1294 |doi=10.1111/cbdd.13049 |url=https://www.ncbi.nlm.nih.gov/pubmed/28639358 |issn=1747-0285}}</ref> |
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=== α keto amide === |
=== α keto amide === |
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Revision as of 19:44, 16 December 2018
Introduction
Lipase inhibitors
Pancreatic, endothelial, hepatic, lipoprotein lipases are types of the human lipase family and have structural similarity. Other tissues like lungs, kidney, skeletal muscles, adipose tissue and placenta also release lipase enzymes. Pancreatic acinar cells secrete pancreatic lipase .An important enzyme of pancreatic juice for digestion of dietary triglycerides in the small intestine.[1]
synthetic pancreatic lipase inhibitor
Synthetic pancreatic lipase inhibitors are new approach have been studied for lipid lowering activity and anti-obesity, in order to decrease side effects of available lipid lowering agents including natural pancreatic lipase inhibitors and to increase the efficacy.[2]
Mechanism of action
Lipase inhibitors bind to lipase enzymes in the intestine so prevent break down of triacylglycerides into free fatty acids and glycerols.It acts on the active site of the enzyme and inhibits it, so preventing the binding of lipids on to the active site of the enzyme. This prevents the hydrolysis of the dietary lipids hindering their absorption through the intestinal membrane. These lipid molecules are excreted via the large intestine. This mechanism is targeted to reduce the amount of body fat and the body weight.[3]
Uses
Obesity
and its related diseases such as diabetes mellitus (DM) and coronary heart diseases are a major concerns in our world. An important approach for the treatment of obesity includes the development of inhibitors of nutrient digestion and absorption. Inhibition of pancreatic lipase and thus reduction of the absorption of fats is an important target for treating obesity and hyperlipidemia.[4][5]
Pancreatic lipase inhibition is the most widely studied method for the identification of potential anti-obesity agents. In the search of pancreatic lipase inhibitor, alot of plant extracts, isolated phyto-constituents, semi-synthetic and synthetic compounds have been screened for their pancreatic lipase inhibitory activity. Many pancreatic lipase inhibitors are under clinical investigations.[6]
Commonly available strategy for analogue synthesis for pancreatic lipase inhibitors depend on the structure of natural substrate of lipase, i.e. triglycerides. 1,3-diaminopropan-2-ol, 2-amino alcohol, glycerol and 2-methylglycerol were commonly utilized as backbone to form a triglyceride kind of molecules with modified more stable and/or hindered ester or amide or ether linkages.[7]
Anti-hyperlipidemic
Elevated blood total cholesterol (TC), elevated low-density lipoprotein cholesterol (LDL-C), and elevated triglyceride (TG) levels have been reported by the World Health Organization (WHO) to contribute to approximately 56% of coronary heart diseases (CHDs) and 18% of cerebrovascular diseases worldwide, which consequently lead to 4.4 million deaths each year.Dyslipidemia is a major risk factor for the development of cardiovascular diseases. Many dyslipidemic patients do not achieve their target lipid levels with the currently available medications, and most of them may experience many side effects. Synthetic pancreatic lipase inhibitors possesse significant antihyperlipidemic activities on lipid components.[8]
Agents under investigation
N-(benzoylphenyl)pyridine-3-carboxamide derivatives
Nicotinic acid is a well-studied agent for lowering TG and LDL-C, and for increasing HDL-C. Unfortunately, despite nicotinic acid can be highly effective and positively acts on lipoprotein profile, especially in individuals with atherogenic dyslipidemia, its usefulness has been reduced by side effects, especially flushing that consequently limit adherence. From this point, new class of nicotinic acid carboxamide derivatives acting as a potential lipid lowering agents starting from nicotinic acid (niacin). The choice of carboxamide derivatives was based on possessing lipid-lowering effects. A hybrid chemical scaffold of two effective hypolipidemic agents using a well-established nucleus (nicotinic acid nucleus) to synthesize a novel nicotinic carboxamide derivative containing the benzophenone unit of fenofibrate drug (Figure 1). This new combination may produce a promising candidate for the treatment of hyperlipidemia with potentially higher potency.[9]
Isonicotinic carboxamide derivatives
Isonicotinic acid (which is an isomer of nicotinic acid) was used as starting point to synthesize novel isonicotinic carboxamide derivatives bearing the benzophenone unit of the fenofibrate drug.A new potential antihyperlipidemic compounds derived from isonicotinic acid N-(3-Benzoylphenyl)pyridine4-carboxamide was found to have promising lipid-lowering and antioxidant effects, which may create a protective effect against cardiovascular disease , by reducing the LDL-C levels and diminishing the generation of reactive oxygen species. N-(3-Benzoylphenyl)pyridine-4-carboxamide and N-(2-Benzoyl-5-methylphenyl)pyridine-4-carboxamide have the most antihyperlipidemic activity , N-(9,10-Dioxo-9,10-dihydroanthracen-2-yl)pyridine-4-carboxamide has the most antioxidant activity. [10]
Fluoroquinolones and triazolofluoroquinolone
Scaffold similarities in the structures of reported pancreatic lipase inhibitors based on isoquinoline and quinolone structures were the basis to investigate the anti-pancreatic lipase activities of the synthetic fluoroquinolones (FQs). In effect, FQs, mostly known as potent and effective antibacterials and recently have been proven to act as potential pancreatic lipase inhibitors. Triazolofluoroquinolones (TFQs) exhibit PL inhibitory activity with appreciable anticancer propensities. Twelve newly synthesized FQs and TFQs were tested with respect to their in vitro antilipase and antiproliferative activities and were evaluated for their antilipolytic efficacy and potency properties. . The PL-IC50 values ( concentration that reduces the effect by 50% ) of 12 FQs and TFQs were in the range of 12.5–189.1 μm. . The IC50 value of the reference compound, orlistat, was 0.2 μm. Table 1 reveals that FQs 4a, 4c, 3b, and 5b exhibited significant inhibitory activity with PL-IC50 values.[11]
α keto amide
Is a lipophilic α-keto amide, inhibitor of pancreatic lipase, was synthesized by using a lipidic 2-amino alcohol as backbone. The chiral intermediate key 2-(tert-butyloxycarbonylamino)-D-undecen-5-ol was synthesized starting from D-glutamic acid.This molecule was shown to decrease 50% of pancreatic lipase activity.[12]
References
- ^ Lunagariya, Nitin A.; Patel, Neeraj K.; Jagtap, Sneha C.; Bhutani, Kamlesh K. (2014). "Inhibitors of pancreatic lipase: state of the art and clinical perspectives". EXCLI journal. pp. 897–921.
- ^ Abu Farha, Rana; Bustanji, Yasser; Al-Hiari, Yusuf; Bardaweel, Sanaa; Al-Qirim, Tariq; Abu Sheikha, Ghassan; Albashiti, Rabab (October 2017). "Pharmacological Evaluation of Novel Isonicotinic Carboxamide Derivatives as Potential Anti-Hyperlipidemic and Antioxidant Agents". Archiv der Pharmazie. 350 (10): 1700024. doi:https://doi.org/10.1002/ardp.201700024.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Schmid, Rolf D.; Verger, Robert (3 July 1998). "Lipases: Interfacial Enzymes with Attractive Applications". Angewandte Chemie (International Ed. in English). pp. 1608–1633. doi:10.1002/(SICI)1521-3773(19980703)37:123.0.CO;2-V.
- ^ Buchholz, Tina; Melzig, Matthias F. (2015). "Polyphenolic Compounds as Pancreatic Lipase Inhibitors". Planta Medica. pp. 771–783. doi:10.1055/s-0035-1546173.
- ^ Martínez, J. Alfredo; Campión, Javier; Boqué, Noemí; Milagro, Fermín I.; Garza, Ana Laura de la (2011). "Natural inhibitors of pancreatic lipase as new players in obesity treatment". undefined.
- ^ Birari, Rahul B.; Bhutani, Kamlesh K. (October 2007). "Pancreatic lipase inhibitors from natural sources: unexplored potential". Drug Discovery Today. 12 (19–20): 879–889. doi:https://doi.org/10.1016/j.drudis.2007.07.024.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Lunagariya, Nitin A.; Patel, Neeraj K.; Jagtap, Sneha C.; Bhutani, Kamlesh K. (22 August 2014). "Inhibitors of pancreatic lipase: state of the art and clinical perspectives". EXCLI Journal. pp. 897–921.
- ^ Abu Farha, Rana; Bustanji, Yasser; Al-Hiari, Yusuf; Bardaweel, Sanaa; Al-Qirim, Tariq; Abu Sheikha, Ghassan; Albashiti, Rabab (October 2017). "Pharmacological Evaluation of Novel Isonicotinic Carboxamide Derivatives as Potential Anti-Hyperlipidemic and Antioxidant Agents". Archiv Der Pharmazie. 350 (10). doi:10.1002/ardp.201700024. ISSN 1521-4184.
- ^ Abu Farha, Rana; Bustanji, Yasser; Al-Hiari, Yusuf; Al-Qirim, Tariq; Abu Shiekha, Ghassan; Albashiti, Rabab (2016). "Lipid lowering activity of novel N-(benzoylphenyl)pyridine-3-carboxamide derivatives in Triton WR-1339-induced hyperlipidemic rats". Journal of Enzyme Inhibition and Medicinal Chemistry. 31 (sup4): 138–144. doi:10.1080/14756366.2016.1222581. ISSN 1475-6374.
- ^ Abu Farha, Rana; Bustanji, Yasser; Al‐Hiari, Yusuf; Bardaweel, Sanaa; Al‐Qirim, Tariq; Abu Sheikha, Ghassan; Albashiti, Rabab (1 August 2017). "Pharmacological Evaluation of Novel Isonicotinic Carboxamide Derivatives as Potential Anti‐Hyperlipidemic and Antioxidant Agents". Archiv der Pharmazie. 350. doi:10.1002/ardp.201700024.
- ^ Arabiyat, Shereen; Kasabri, Violet; Al-Hiari, Yusuf; Bustanji, Yasser K.; Albashiti, Rabab; Almasri, Ihab M.; Sabbah, Dima A. (December 2017). "Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones". Chemical Biology & Drug Design. 90 (6): 1282–1294. doi:10.1111/cbdd.13049. ISSN 1747-0285.
- ^ "Synthesis and Study of a Lipophilicα-Keto Amide Inhibitor of Pancreatic Lipase". Chiou, A., Markidis, T., Constantinou-Kokotou, V., Verger, R. and Kokotos, G. (2000). Synthesis and Study of a Lipophilicα-Keto Amide Inhibitor of Pancreatic Lipase. Organic Letters, 2(3), pp.347-350.