Discovery Approaches for Novel Dyslipidemia Drugs

Abstract

Statins are, currently available, best choice of drugs for treating dyslipidemia and coronary diseases. In addition to this, lipid lowering drugs support treatment to a great extent, either as monotherapy or in combinations with other groups. Pravastatin used in combination with cholesteryl ester, transfers protein inhibitors (CETP) to produce efficient results. Peroxisome proliferator-activated receptor agonists (PPAR) like muraglitazar, aleglitazar and tesaglitazar are PPAR α/γ receptor agonist, dual in action performs better in phase 3 clinical study and reduces renal and cardiovascular events. By targeting both receptors, a better treatment for cardiovascular and diabetic problems can be achieved. Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors like humanized monoclonal antibodies, are newly discovered inhibitors that reduce the risk of cardiovascular diseases. During the past few years, nucleic acid-based therapies targeting lipid and lipoprotein metabolism, such as microsomal TG transfer protein (MTP) may be a promising therapeutic approach to treat vascular diseases. Gene regulating transcription factors involved in bile acids and cholesterol metabolism can be controlled by FXR agonists in dyslipidemia. To overcome these drawbacks, many thyroid hormone analogues have been developed to lower down cholesterol level by targeting specifically thyroid hormone β receptors abundantly present in the liver without severe side effects. Virtual screening, an important tool in screening databases of the lead compounds, provides a good platform to access new compounds. In this review, examples of novel FXR modulators, thyromimetic agents, cholesterol absorption inhibitors and other new anti hyperlipidemia scaffolds have been addressed.

The CD36-PPARγ Pathway in Metabolic Disorders

“…As a result, some TZDs have been withdrawn from clinics due to life-threatening hepatic toxicity, while serious safety warnings were recently issued for others [ 26 , 27 , 28 ]. While strategies to develop safer PPAR pan/dual agonists are of continuous interest [ 29 , 30 ], it has become a fundamental priority to identify other treatment strategies in order to avoid the adverse effects of PPAR ligands while keeping the benefits of correcting whole body glucose and cardiovascular dysfunctions. Our recent identification of PPARγ as a new target of CD36 signaling might feed into the development of potential alternatives in the beneficial control of lipid metabolism.…”

Alteration of lipid metabolism in chronic kidney disease, the role of novel antihyperlipidemic agents, and future directions

“…As such, CETP inhibition via monoclonal antibodies, vaccines, and antisense oligonucleotides remains of major clinical interest (Shrestha et al, 2018). There are numerous emerging therapies including icosapent-etyhl (Bhatt et al, 2017), bempedoic acid (Pinkosky et al, 2016;Ray et al, 2019), Apo C-III (a key regulator in hypertriglyceridemia) inhibition (Rocha et al, 2017) and novel cellular binding proteins (Maqbool et al, 2015), that are being studied as tailored tools to combat dyslipidemia-their effect in the CKD population has yet to be determined. A brief summary of hyperlipidemic treatment options (including a few therapies not mentioned above) is provided in Table. 2 (Einarsson et al, 1991;Fares et al, 2014;Grundy et al, 2018;Kamanna and Kashyap, 2008;KDIGO, 2013;Ray et al, 2019;Shearer et al, 2012).…”