The combination of niacin with a selective
The combination of niacin with a selective PGD2 receptor antagonist laropiprant, designed to circumvent the flushing side effect of niacin, has been evaluated in the HPS2-THRIVE study and showed no clinically meaningful benefit when administered in patients on top of statin therapy . Our data suggest that prostanoids released from macrophages in response to niacin may play an important role in mediating its beneficial effect. Laropiprant administered together with niacin may have blocked the contribution of macrophage-released prostanoids to the cAMP-mediated modulation of reverse cholesterol transport described above, thus negating the macrophage mediated anti-atherosclerotic activity of niacin. More studies are needed to test viability of development of GPR109A targeted therapies which are devoid of niacin-like flushing side effects but retain macrophage mediated anti-atherosclerotic activities and may provide further insight into this aspect of the niacin mechanism.
Nicotinic FPS-ZM1 sale (Niacin) is a drug that has been extensively used in clinical practice for more than 50 years to reduce heart disease, by elevating high density lipoprotein cholesterol (HDL-C) and lowering low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and free fatty acids (FFA). However, it requires high dosages, and the beneficial effects are accompanied by the uncomfortable side effects of flushing (vasodilatation), which limits patient compliance. In 2003, three groups independently identified GPR109A, a G protein coupled receptor (GPCR), as a specific and high affinity receptor for nicotinic acid. Two other receptors have been discovered that are related to GPR109A: GPR109B (89% sequence identity with GPR109A) which is a low affinity nicotinic acid receptor, and GPR81 (49% sequence identity with GPR109A). Given the well-demonstrated benefit of nicotinic acid, the discovery of nicotinic acid receptors has stirred great interest in pursuing GPR109A agonists,, as potential therapeutic agents that might possess similar cardiovascular benefit to nicotinic acid while avoiding flushing. GPR109A belongs to the family A GPCRs. GPCRs are trans-membrane proteins, sharing a common three-dimensional topology that consists of seven trans-membrane helices (7TMs) and one cytoplasmic helix, helix 8. The 7TMs are connected by three extra-cellular loops (ECLs) and three intra-cellular loops (ICLs). Sequence information for GPCRs is abundant, with ∼9000 receptor sequences available. In contrast, structural information is limited to two family A GPCRs: over 10 bovine rhodopsin structures determined from 2000 to date,, and two human β-adrenoceptor (βAR) structures solved in 2007. The limited structural information makes molecular modeling of GPCRs as an important approach for structure–function studies and for drug design. The known X-ray crystal structures have provided attractive templates for homology modeling of family A GPCRs, and there are many examples in which the crystal structures of bovine rhodopsin have been successfully applied as templates. Here, we describe a molecular model of GPR109A bound to an anthranilic acid derivative, (), which was identified in a high throughput screen (HTS), and is a weak GPR109A agonist (). The homology model was constructed based on the X-ray crystal structure of bovine rhodopsin (PDB entry 1L9H), which was the best template at the time we carried out this study. Compound was docked into the putative binding pocket of GPR109A. Grid-based surface calculations of the docking model provided a clear visualization of the characterization of the binding pocket, which has aided design of compounds with significantly improved potency.
Nicotinic acid (niacin) has been a leading treatment for dyslipideamia and for the prevention of atherosclerosis for over 40 years. Long term clinical studies have revealed niacin’s ability to reduce 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., 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 have limited such investigations.