ABSTRACT
The parabolic wave equation is solved using a finite-difference solution in depth that involves a nonuniform grid. The depth operator is discretized using Galerkin's method with asymmetric hat functions. Examples are presented to illustrate that this approach can be used to improve efficiency for problems in ocean acoustics and seismo-acoustics. For shallow water problems, accuracy is sensitive to the precise placement of the ocean bottom interface. This issue is often addressed with the inefficient approach of using a fine grid spacing over all depth. Efficiency may be improved by using a relatively coarse grid with nonuniform sampling to precisely position the interface. Efficiency may also be improved by reducing the sampling in the sediment and in an absorbing layer that is used to truncate the computational domain. Nonuniform sampling may also be used to improve the implementation of a single-scattering approximation for sloping fluid-solid interfaces.
Subject(s)
Acoustics , Models, Theoretical , Sound , Water , Absorption , Geologic Sediments , Motion , Oceans and Seas , Pressure , Scattering, Radiation , Signal Processing, Computer-Assisted , Sound Spectrography , Surface Properties , Time FactorsABSTRACT
Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the alpha-thrombin-hirugen complex provides an explanation for these unanticipated results.
Subject(s)
Amides/chemistry , Antithrombins/pharmacology , Antithrombins/chemistry , Crystallography, X-Ray , Molecular StructureABSTRACT
Starting from a 2-amino-6-methylpyridine P1 group and following a strategy of enlarging it whilst reducing its polarity, we have developed a series of potent, moderately basic azaindoles which are intrinsically much more selective for thrombin versus trypsin. Certain pyrazinone acetamide azaindole derivatives have pharmacokinetic parameters after oral administration to dogs, or efficacy in vitro, comparable to an optimized pyrazinone acetamide 2-amino-6-methylpyridine derivative.
Subject(s)
Aza Compounds/chemistry , Aza Compounds/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Indoles/pharmacology , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Aza Compounds/pharmacokinetics , Dogs , Enzyme Inhibitors/pharmacokinetics , Humans , Indoles/pharmacokinetics , Models, Molecular , Partial Thromboplastin Time , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity Relationship , Substrate Specificity , Thrombin/metabolism , Trypsin/metabolismABSTRACT
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
