ABSTRACT
A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.
Subject(s)
Indenes/pharmacology , Pyrazoles/pharmacology , Administration, Oral , Animals , Chemistry, Pharmaceutical , Drug Design , Edema/pathology , Estradiol/pharmacology , Female , Indenes/chemistry , Inhibitory Concentration 50 , Mice , Models, Chemical , Models, Molecular , Pyrazoles/chemistry , Structure-Activity Relationship , Uterus/drug effects , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
We report the synthesis of kinase targeted libraries based on the thienopyrazole scaffold. Several thienopyrazole analogs have been identified as submicromolar inhibitors of KDR.
Subject(s)
Chemistry, Pharmaceutical/methods , Drug Design , Enzyme Inhibitors/pharmacology , Phosphotransferases/chemistry , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Models, ChemicalABSTRACT
We report the discovery of a novel class of macrolide antibiotics that have improved antibacterial activity against Ery-resistant organisms.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacteria/drug effects , Erythromycin/pharmacology , Macrolides/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/metabolism , Cell Membrane/metabolism , Drug Resistance , Drug Resistance, Bacterial , Macrolides/pharmacology , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to increase serum lithium concentrations. We sought to determine whether NSAIDs that selectively inhibit cyclooxygenase (COX) 2 also elevate serum lithium concentrations. METHOD: The U.S. Food and Drug Administration's Adverse Event Reporting System (AERS) database was searched in January 2003 for reports of interactions between lithium and rofecoxib or celecoxib, the selective COX-2 inhibitors marketed in the United States. Additionally, a literature search was performed using PubMed with the MeSH terms anti-inflammatory agents, nonsteroidal and lithium. Reports of interactions between NSAIDs and lithium were selected for review based on titles of retrieved citations. RESULTS: Eighteen cases of increased serum lithium concentrations after the addition of one of the COX-2 inhibitors to stable lithium therapy were retrieved from AERS, 13 with rofecoxib and 5 with celecoxib. Serum lithium concentration increases of up to 99% and 448% with concomitant celecoxib and rofecoxib use, respectively, were reported. Thirty-six English-language literature articles report interactions between lithium and various NSAIDs. Although some articles report no effect or decreased serum lithium concentrations with concomitant aspirin or sulindac, increased serum lithium concentration reports exist for aspirin, sulindac, and 14 other NSAIDs, including celecoxib and rofecoxib. CONCLUSION: Clinicians should consider NSAID use in the differential diagnosis of lithium toxicity, monitor patients' serum lithium concentrations during the initiation or discontinuation of NSAID therapy, and be aware that the selective COX-2 inhibitors can increase serum lithium concentrations leading to toxicity.
Subject(s)
Adverse Drug Reaction Reporting Systems/statistics & numerical data , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antimanic Agents/adverse effects , Antimanic Agents/blood , Cyclooxygenase Inhibitors/adverse effects , Cyclooxygenase Inhibitors/pharmacology , Lactones/adverse effects , Lactones/pharmacology , Lithium Carbonate/adverse effects , Lithium Carbonate/blood , Sulfonamides/adverse effects , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , Celecoxib , Drug Interactions , Female , Humans , Male , Middle Aged , Pyrazoles , Sulfones , United States , United States Food and Drug AdministrationABSTRACT
[reaction: see text] The application of microwave heating to a polymer-assisted solution-phase (PASP) synthesis technique has been utilized to develop a rapid and efficient protocol for the solution-phase synthesis of amides from either amine or carboxylic acid cores.
