Aventis Pharma Deutschland, Gmbh

Aventis Pharmaceuticals Inc.

Protein Technologies, Inc.

Selectide Corporation

Nanoscale Combinatorial Synthesis, Inc.

James A Ostrem

Armin Walser

Fahad A Al-Obeidi

Gerhard Zoller

Elisabeth Defossa

Otmar Klingler

Pavel Safar

Michal Lebl

Peter Strop

Alena Stierandova

Milan Bier

Terry D Long

Nikolai Sepetov

Olga L Issakova

Stephen A Baum

Rodolfo B Marguez

The present invention includes methods for generating combinatorial libraries on solid phase supports in which increased productivity is achieved by pooling all common steps in synthesis without using a tracking or coding system to record the synthetic history of each compound. Methods for generating combinatorial libraries in which containers with random mixtures of solid phase particles are divided and combined together in non-random ways without the exchange of particles between containers are also provided. Various products are optionally produced in multi-stage syntheses according to the invention, such as oligomers and synthetic non-repetitive organic molecules. The methods additionally relate to the identification of each library component without adding extra synthetic, physical, optical, or electronic encoding steps during library synthesis. Combinatorial synthetic systems are also provided.

Nonredundant split/pool synthesis of combinatorial libraries

The invention provides compounds which specifically inhibit factor Xa activity having the structure A &mdash;A &mdash;(A ) &mdash;B, where m is 0 or 1. A compound of the invention is characterized, in part, in that it exhibits a specific inhibition of factor Xa activity with a K &lE;100 &mgr;M, preferably &lE;2 nM, and does not substantially inhibit the activity of other proteases involved in the coagulation cascade. The invention further provides methods of specifically inhibiting the activity of factor Xa and of inhibiting blood clotting in vitro and in an individual and methods of detecting factor Xa levels or activity.

Factor Xa inhibitors

N-guanidinoalkylamides, their preparation, their use, and pharmaceutical preparations comprising them

The invention provides compounds which specifically inhibit factor Xa activity. The compounds consist of the structure X.sub.1 -YIR-X.sub.2, wherein X.sub.1 is H, acyl, alkyl, acylalkyl, arylalkyl or one or more amino acids, and X.sub.2 is a modified C-terminal group, one or more carboxy-protecting groups or one or more amino acids or other substituent, and Y, I and R are tyrosine, isoleucine and arginine, respectively, or peptidomimetic or organic structures that possess the same functional activity as Y, I and R, respectively. In addition, the present invention provides a compound having the structure A1-A2-(A3).sub.m --B, where m is 0 or 1. A compound of the invention can be linear or cyclic and can be about 2 and 43 residues in length. A compound of the invention is characterized, in part, in that it exhibits a specific inhibition of factor Xa activity with a K.sub.i of .ltoreq.100 .mu.M, preferably .ltoreq.2 nM, and does not substantially inhibit the activity of other proteases involved in the coagulation cascade. The invention further provides methods of specifically inhibiting the activity of factor Xa and of inhibiting blood clotting in vitro and in an individual and methods of detecting factor Xa levels or activity.

A novel pH buffering system which is functionally stable under electrophoretic conditions employs buffering components in complementary buffer pairs. The buffering components are selected from among simple chemically defined ampholytes, weak acids and weak bases, and are paired together on the basis of their dissociation characteristics to define narrow overlapping buffering zones in which the buffering components exhibit low net electrophoretic mobility combined with desired pH buffering capacity. The narrow buffering zones cover from 0.4 to 1.25 pH units within a broad range of pH values of from about pH 3 to about pH 10. Specific buffering pH values within the narrow buffering zones are obtainable by varying the molar ratios of the two buffering components of the selected buffer pair. The buffering system may be used to form functionally stable precast narrow pH zone gradients in free solution, and has particular utility in isoelectric focusing and other electrophoretic processes.

Buffering system and its use in electrophoretic processes

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Tucson, AZ, United States of America

James A Ostrem