Isis Pharmaceuticals, Inc.

Johnson & Johnson Pharmaceuticals Research & Development, L.l.c.

Venkatraman Mohan

Muthiah Manoharan

Richard Holmes Griffey

Eric E Swayze

Phillip Dan Cook

Thazha P Prakash

Vasulinga T Ravikumar

Yili Ding

Steven A Hofstadler

David J Ecker

Stanley T Crooke

Tianbao Lu

Kevin Douglas Kreutter

John McNeil

Andrew Mamoru Kawasaki

Guozhang Xu

Jared James Drader

Hui Huang

Lily Lee

Sharmila Patel

Kristin Sannes Lowery

Ranga Sampath

Herb Boswell

Mark Fitzgerald

Phenyl acetamide compounds are described, including compounds of Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein R-R, R, B, Y and W are set forth in the specification. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as thrombin and factor Xa. Compositions for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation are described. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.

Substituted phenyl acetamides and their use as protease inhibitors

Modified oligonucleotides containing both A-form conformation geometry and B-from conformation geometry nucleotides are disclosed. The B-form geometry allows the oligonucleotide to serve as substrates for RNase H when bound to a target nucleic acid strand. The A-form geometry imparts properties to the oligonucleotide that modulate binding affinity and nuclease resistance. By utilizing C2' endo sugars or O4&#x2032; endo sugars, the B-form characteristics are imparted to a portion of the oligonucleotide. The A-form characteristics are imparted via use of either 2&#x2032;-O-modified nucleotides that have 3&#x2032; endo geometries or use of end caps having particular nuclease stability or by use of both of these in conjunction with each other.

Oligonucleotides having A-DNA form and B-DNA form conformational geometry

Methods for the identification of compounds which modulate, either inhibit or stimulate, biomolecules are provided. Nucleic acids, especially RNAs are preferred substrates for such modulation. The present methods are particularly powerful in that they provide novel combinations of techniques which give rise to compounds, usually 'small' organic compounds, which are highly potent modulators of RNA and other biomolecular activity. In accordance with preferred aspects of the invention, very large numbers of compounds may be tested essentially simultaneously to determine whether they are likely to interact with a molecular interaction site and modulate the activity of the biomolecule. Pharmaceuticals, veterinary drugs, agricultural chemicals, industrial chemicals, research chemicals and many other beneficial compounds may be identified in accordance with embodiments of this invention.

Molecular interaction sites of interleukin-2 RNA and methods of modulating the same

The present invention is directed to analogs of aminoglycoside compounds of the class having a glycosylated 2-deoxystreptamine (2-DOS) ring as well as their preparation and use as prophylactic or therapeutics against microbial infection. Compounds of the invention comprises at least one aryl, heteroaryl, substituted aryl or substituted heteroaryl group in place of a glycosyl group attached to the 2-deoxystreptamine ring.

Antimicrobial 2-deoxystreptamine compounds

The present invention provides oligomers which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the nucleoside moieties of the oligomer is modified to include a guanidinium group. These oligomers are useful for diagnostic, therapeutic and investigative purposes.

Guanidinium functionalized intermediates

The present invention provides methods for the identification ligand compounds that bind to target molecules such as proteins or structured RNA with as little as millimolar (mM) affinity using mass spectrometry. The methods may be used to determine the mode of binding interaction between two or more of these ligand compounds to the target as well as their relative affinities. Also provided are methods for designing compounds having greater affinity to a target molecule by identifying two or more ligands using mass spectrometry methods of the invention and linking the ligands together to form a novel compound.

Optimization of ligand affinity for RNA targets using mass spectrometry

Modified oligonucleotides containing both A-form conformation geometry and B-from conformation geometry nucleotides are disclosed. The B-form geometry allows the oligonucleotide to serve as substrates for RNase H when bound to a target nucleic acid strand. The A-form geometry imparts properties to the oligonucleotide that modulate binding affinity and nuclease resistance. By utilizing C2&prime; endo sugars or O4&prime; endo sugars, the B-form characteristics are imparted to a portion of the oligonucleotide. The A-form characteristics are imparted via use of either 2&prime;-O-modified nucleotides that have 3&prime; endo geometries or use of end caps having particular nuclease stability or by use of both of these in conjunction with each other.

Guanidinium functionalized nucleotides and precursors thereof

Guanidinium functionalized oligonucleotides and method/synthesis

2&prime;-O-modified ribosyl nucleosides and modified oligonucleotides containing such nucleotides are disclosed. Oligonucleotides are disclosed that have increased binding affinity as shown by molecular modeling experiments. The 2&prime;-O-modified nucleosides of the invention include ring structures that position the sugar moiety of the nucleosides preferentially in 3&prime; endo geometries.

RNA targeted 2&prime;-modified oligonucleotides that are conformationally preorganized

Novel .beta.-lactam monomers bearing various functional groups are prepared. The novel .beta.-lactam monomers can be joined into oligomeric compounds such as via preferred phosphate linkages including phosphodiester and phosphorothioate linkages. Useful functional groups include nucleobases as well as polar groups, hydrophobic groups, ionic groups, aromatic groups and/or groups that participate in hydrogen bonding. The oligomeric compounds are useful as diagnostic and research reagents.

Lactam nucleic acids

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Carlsbad, CA, United States of America

Venkatraman Mohan