ABSTRACT
The inbuilt 2-N-hydroxy-1-oxo-3-carboxylic acid of isoquinolone was designed as pyrophosphate mimic for hepatitis C NS5B polymerase. Various 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid derivatives 11a-p were synthesized and evaluated as HCV NS5B polymerase inhibitors. Compound 11c exhibited moderate inhibitory potency based on the inorganic pyrophosphate generation (IC50 = 9.5 µM) and based on NTP incorporation by NS5B enzyme (IC50 = 5.9 µM). Compound 11c demonstrated antiviral activity (EC50 = 15.7 µM) and good selectivity in HCV genotype 1b replicon Ava.5 cells. Compound 11c reduced the interaction of NTP to NS5B polymerase. Docking model showed that 11c situated in similar orientation to the bound uridine triphosphate in the active site of NS5B polymerase. As a result, 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid was disclosed as a novel inbuilt ß-N-Hydroxy-γ-keto-acid pharmacophore for HCV NS5B polymerase inhibitors.
Subject(s)
Carboxylic Acids/pharmacology , Enzyme Inhibitors/pharmacology , Isoquinolines/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Keto Acids , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
Hepatitis C virus (HCV), a causative agent for non-A and non-B hepatitis, has infected approximately 3% of world's population. The current treatment option of ribavirin in combination with pegylated interferon possesses lower sustained virological response rates, and has serious disadvantages. Unfortunately, no prophylactic vaccine has been approved yet. Therefore, there is an unmet clinical need for more effective and safe anti-HCV drugs. HCV NS5B RNA dependent RNA polymerase is currently pursued as the most popular target to develop safe anti-HCV agents, as it is not expressed in uninfected cells. More than 25 pharmaceutical companies and some research groups have developed ≈50 structurally diverse scaffolds to inhibit NS5B. Here we provide comprehensive account of the drug development process of these scaffolds. NS5B polymerase inhibitors have been broadly classified in nucleoside and non nucleoside inhibitors and are sub classified according to their mechanism of action and structural diversities. With some additional considerations about the inhibitor bound NS5B enzyme X-ray crystal structure information and pharmacological aspects of the inhibitors, this review summarizes the lead identification, structure activity relationship (SAR) studies leading to the most potent NS5B inhibitors with subgenomic replicon activity.
Subject(s)
Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , Hepatitis C/drug therapy , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemistry , Amides/therapeutic use , Antiviral Agents/therapeutic use , Azoles/chemistry , Azoles/therapeutic use , Clinical Trials as Topic , Enzyme Inhibitors/therapeutic use , Humans , Nucleosides/chemistry , Nucleosides/therapeutic use , Pyrimidines/chemistry , Pyrimidines/therapeutic use , RNA-Dependent RNA Polymerase/metabolism , Viral Nonstructural Proteins/metabolismABSTRACT
Pseudohyperkalaemia in conditions with increased platelet counts is caused by an in vitro rise of the serum potassium concentration during whole blood coagulation and the lysis of the platelets and other cellular components, in the presence of normal renal function and normal plasma potassium levels. The association between pseudohyperkalaemia and aetiology of thrombocytosis was studied in a 6-year retrospective audit on 90 patients with thrombocytosis referred to the Haematology Department in Ulster Hospital Dundonald, a large district general hospital. Over two-thirds of this study population had myeloproliferative disorders, and the most common diagnosis was primary thrombocythaemia (41%, n = 37). Reactive thrombocytosis was observed in approximately one-third of the cases (32%, n = 29). Pseudohyperkalaemia with apparent potassium level above the upper limit of the normal range (reference range K 3.5-5.1 mmol/l) was observed in the majority of patients with thrombocytosis from any aetiology (60%, n = 54). The likelihood of finding pseudohyperkalaemia was highest among patients with primary thrombocythaemia (75.7%, n = 28/37) and polythaemia rubra vera (75%, n = 12/16), followed by myelofibrosis (50%, 4/8) and reactive thrombocytosis (34.5%, n = 10/29). A highly significant positive correlation was observed between the platelet counts and the serum potassium level (Spearman's correlation coefficient, R = 0.998, P = 0.01). Awareness of pseudohyperkalemia in disease conditions with increased platelet counts will lead to the withholding of potentially harmful treatment.
Subject(s)
Hyperkalemia/etiology , Myeloproliferative Disorders/complications , Adult , Aged , Aged, 80 and over , Female , Humans , Hyperkalemia/diagnosis , Male , Middle Aged , Platelet Count , Potassium/blood , Retrospective Studies , Thrombocytosis/complicationsABSTRACT
We present a case of 22 year old female who had pulmonary tuberculosis followed by tuberculous meningitis and tuberculomas in past. This time she presented to us with right hemiparesis and altered sensorium. Diagnosis of tumefactive demyelination was made on the basis of typical MRI findings. Patient showed good response to steroids.
