ABSTRACT
The grey mullet usually occur in large numbers and biomass in the estuaries of all three South African biogeographic regions, thus making it an ideal family to use in terms of possibly acting as an environmental indicator of global warming. In this analysis the relative estuarine abundance of the dominant three groups of mugilids, namely tropical, warm-water and cool-water endemics, were related to sea surface coastal temperatures. The study suggests a strong link between temperature and the distribution and abundance of the three mullet groups within estuaries and indicates the potential of this family to act as an indicator for future climate change within these systems and adjacent coastal waters.
Subject(s)
Climate Change , Environmental Monitoring/methods , Estuaries , Global Warming , Smegmamorpha/physiology , AnimalsABSTRACT
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
Subject(s)
Imidazoles/chemistry , Janus Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Animals , Cell Line , Janus Kinase 1/chemistry , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/chemistry , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Substrate SpecificityABSTRACT
Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.
Subject(s)
Amides , Piperidines , Serine Endopeptidases/drug effects , Administration, Oral , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Biological Availability , Caco-2 Cells , Crystallography, X-Ray , Drug Design , Factor Xa Inhibitors , Humans , Liver/enzymology , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Protein Conformation , Rats , Recombinant Proteins/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , TryptasesABSTRACT
The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.
Subject(s)
Adjuvants, Immunologic/chemistry , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/immunology , Animals , Binding Sites , Cell Division/drug effects , Drug Design , Edema/drug therapy , Enzyme Inhibitors/chemistry , Indoles/chemistry , Inhibitory Concentration 50 , Interleukin-2/pharmacology , Janus Kinase 3 , Mice , Oxyquinoline/chemistry , Phosphorylation/drug effects , Protein Binding , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).
