ABSTRACT
Anticoagulants are used to prevent the formation and extension of blood clots in various disorders as prophylactic agents for thrombo-embolic disorders. Designing of specific inhibitors against molecular targets that play a pivotal role in the coagulation cascade is indispensable. Clotting Factor Xa is one such attractive target for the design of new oral anticoagulants because of the unique role factor Xa plays in the coagulation cascade as a connection between the extrinsic and intrinsic pathways. Application of computational techniques in drug discovery process helps in identifying parameters which can lead to achieve better pharmacological profile. The docking interactions and QSAR studies performed on series of 4-methy-3-(6-[phenyl methylene] amino} pyridine-3-yl)-2H chromen-2-one derivatives provide significant insights for designing of better ligands as anticoagulants.
Subject(s)
Aminopyridines/pharmacology , Anticoagulants/pharmacology , Blood Coagulation Factor Inhibitors/pharmacology , Coumarins/pharmacology , Factor Xa Inhibitors , Aminopyridines/chemical synthesis , Aminopyridines/chemistry , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Blood Coagulation Factor Inhibitors/chemical synthesis , Blood Coagulation Factor Inhibitors/chemistry , Coumarins/chemical synthesis , Coumarins/chemistry , Drug Discovery , Linear Models , Models, Molecular , Molecular Structure , Quantitative Structure-Activity RelationshipABSTRACT
Highly active antiretroviral therapy (HAART) significantly decreases plasma viral load, increases CD4+ T-cell counts in HIV-1-infected patients and has reduced progression to AIDS in developed countries. However, adverse side effects, and emergence of drug resistance, mean there is still a demand for new anti-HIV agents. The HIV integrase (IN) is a target that has been the focus of rational drug design over the past decade. In 2007, raltegravir was the first IN inhibitor approved by the US Food and Drug Administration for antiretroviral combination therapy, while another IN inhibitor, elvitegravir, is currently in Phase III clinical trials. This article reviews the development and resistance profiling of small molecule HIV-1 IN inhibitors.
Subject(s)
Drug Discovery , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , Drug Resistance, Viral/drug effects , HIV Infections/drug therapy , HIV Infections/virology , HIV Integrase Inhibitors/adverse effects , HumansABSTRACT
Simvastatin is used in treatment of hypercholesterolemia because it regulates cholesterol synthesis as a result of its ß-hydroxy acid acting as an inhibitor of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA). The present communication deals with synthesis, characterization and development of accurate, precise and sensitive Reverse Phase High Performance Liquid Chromatography (RP-HPLC) method for simultaneous estimation of simvastatin and its synthetic impurities. The impurities methyl ether and ß-hydroxy acid of simvastatin were synthesized in the laboratory and characterized by MS, NMR and FT-IR spectroscopy. The separation of simvastatin and its impurities was carried out on an isocratic JASCO RP-HPLC system using KYA TECH HIQ SIL C(18) column (150 × 4.6 mm internal diameter, particle size 5 µm) operating at ambient temperature using acetonitrile:water (80:20 v/v) with 0.1% orthophosphoric acid as mobile phase. The method developed for HPLC analysis of three impurities along with simvastatin was validated using ICH Q2B (R1) guidelines and it complied with these guidelines. The results of analysis were found to be in the range of 98.14% to 101.89% for all analytes with acceptable accuracy and precision. The method can be used for detection and quantification of synthetic impurities in bulk or formulations of simvastatin.
