Isis Pharmaceuticals, Inc.

Am Chemicals LLC

Other

Medtronic, Inc.

Mcgill University

Mbc Pharma, Inc.

Glen Research Corporation

Andrei P Guzaev

Muthiah Manoharan

Vasulinga T Ravikumar

Douglas L Cole

Daniel C Capaldi

Achim H Krotz

Zhiwei Wang

Raju K Kumar

Vladimir Y Vvedenskiy

Michael E Jung

George Just

Jianchao Wang

Khirud Gogoi

Phillip Dan Cook

Martin A Maier

Balkrishen Bhat

William Frederick Kaemmerer

Brian Dale Nelson

Alexander Karpeisky

Shawn Patrick Zinnen

Matthew H Adams

David Kent Stiles

Douglas Ulen Gwost

Alex Azhayev

Harri Lonnberg

Pei Ge

Arlène Roland

Murali Urlam

Vladimir Y Vvedensky

Arl&egrave;ne Roland

Don Marshall Gash

Dinah W Y Sah

Gregory Robert Stewart

Achim Krotz

Novel non-nucleoside solid supports and phosphoramidite building blocks for preparation of synthetic oligonucleotides containing at least one non-nucleosidic moiety conjugated to a ligand of practical interest and synthetic processes for making the same are disclosed. Furthermore, oligomeric compounds are prepared using said solid supports and phosphoramidite building blocks, preferably followed by removal of protecting groups to provide oligonucleotides conjugated to ligands of interest.

Solid supports and phosphoramidite building blocks for oligonucleotide conjugates

Methods of preparing synthetic oligonucleotides containing at least one phosphotriester linkage conjugated to a monosaccharide are disclosed, where the synthetic oligonucleotides are prepared from nucleosidic phosphoramidite building blocks, preferably followed by removal of protecting groups to provide monosaccharide-conjugated oligonucleotides.

Phosphoramidite building blocks for sugar-conjugated oligonucleotides

Novel nucleoside phosphoramidite building blocks for preparation of synthetic oligonucleotides containing at least one phosphotriester linkage conjugated to a monosaccharide and synthetic processes for making the same are disclosed. Furthermore, oligomeric compounds are prepared using said building blocks, preferably followed by removal of protecting groups to provide monosaccharide-conjugated oligonucleotides.

Compounds and compositions are provided, as are methods of using them to treat infections, neoplastic disease, including pancreatic cancer, inflammatory disease, and pain. Such compounds are nucleotides, acyclonucleotides, and ANP phosphonates conjugated with forms and/or moieties of Vitamin Bfor delivery past the cell membrane and into the cell.

Vitamin B6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates

This invention provides treatment compositions as well as systems and methods of determining and administering an effective amount of treatment for a neurological disorder. The treatment composition can contain a labeled interfering RNA (iRNA) agent capable of decreasing expression of a target RNA associated with the neurological disorder. The methods of the invention include determining an effective amount of a therapeutic composition by introducing a solution containing a tracer into the brain of a mammal. The tracing solution is monitored until a target volume of distribution at steady state distribution is substantially achieved, and the rate of delivery of the therapeutic composition is determined. The therapeutic composition can then be administered at the rate determined by use of the tracing solution.

Treatment of neurological disorders

The use of N-formamidino-5-amino-3H-1,2,4-dithiazole-3-thiones, 5-phenyl-3H-1,2,4-dithiazole-3-thiones, and derivatives thereof as novel, efficient sulfur-transfer reagents is disclosed. Sulfur transfer from these reagents to compounds containing a P(III) atom (e.g., triphenylphosphine, 5'-O-DMT-thymidine 2-cyanoethyl-(N,N-diisopropyl)phosphoramidite, and 5&#x2032;-O-DMT-3&#x2032;-O-levulinyl dithymidilyl 2-cyanoethyl phosphite), was studied in solution byP NMR and HPLC. The sulfur transfer from title compounds was also studied in the solid-phase synthesis of oligonucleotide phosphorothioates by phosphoramidite methods. In this application, the efficiency of the sulfur transfer reaction for 2&#x2032;-deoxyoligonucleotides was better than 99.5%. The novel sulfurizing agents are synthesized, at low cost, using simple chemical methods. As opposed to many sulfur transfer reagents known in the prior art such as 1,2-benzodithiol-3-one-1,1-dioxide (Beaucage reagent) and 5-ethoxy-3H-1,2,4-dithiazole-2-one (EDIT), the sulfurizing agents disclosed herein are highly stable in solution, which increases their practical and commercial value.

Sulfur transfer reagents for oligonucleotide synthesis

Universal linkers, their facile processes of manufacture and methods of using the same are provided.

Supports for oligomer synthesis

The use of N-formamidino-5-amino-3H-1,2,4-dithiazole-3-thiones as novel, efficient sulfur-transfer reagents is disclosed. The sulfur transfer from these reagents to compounds containing P(III) atom, triphenylphosphine, 5'-O-DMT-thymidine 2-cyanoethyl-(N,N-diisopropyl)phosphoramidite, and 5&#x2032;-O-DMT-3&#x2032;-O-levulinyl dithymidilyl 2-cyanoethyl phosphite, was studied in solution byP NMR and HPLC. The sulfur transfer from title compounds was also studied in the solid-phase synthesis of oligonucleotide phosphorothioates by phosphoramidite methods. In this application, the efficiency of the sulfur transfer reaction for 2&#x2032;-deoxyoligonucleotides was better than 99.5%. The novel sulfurizing agents are synthesized, at low cost, using simple chemical methods. As opposed to many sulfur transfer reagents known in the prior art such as 1,2-benzodithiol-3-one-1,1-dioxide (Beaucage reagent) and 5-ethoxy-3H-1,2,4-dithiazole-2-one (EDIT), the sulfurizing agents disclosed herein are highly stable in solution, which increases their practical and commercial value.

Synthetic processes are provided wherein oligomeric compounds are prepared having phosphodiester, phosphorothioate, phosphorodithioate, or other covalent linkages. The oligomers have substantially reduced exocyclic adducts deriving from acrylonitrile or related contaminants.

Process for the synthesis of oligomeric compounds

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Vista, CA, United States of America

Andrei P Guzaev