Roche Diagnostics Operations, Inc.

Arrowhead Pharmaceuticals, Inc.

Arrowhead Madison, Inc.

Wilma Thuer

Dieter Heindl

Peter Mohr

David B Rozema

Darren H Wakefield

Philipp Hadwiger

Christoph Seidel

David L Lewis

Angelika Roesler

Dirk Kessler

Linda Valis

Torsten Hoffmann

Eric Argirios Kitas

Torsten Hoffman

Erik Kitas

Linda Christine Valis

The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted delivery polymers. Delivery polymers provide membrane penetration function for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness to the delivery polymers.

Compositions for targeted delivery of siRNA

The trivalent phosphorous atom of a compound is reacted with a reagent in such a manner that a stable phosphate mimetic or a specifier is formed. Phosphoramidites with a phosphorous atom containing at least one hydroxyl residue which is provided with a protective group are reacted for this purpose with a free hydroxyl group: In the first synthesis cycle the hydroxyl group is linked to a solid support via a cleavable or non-cleavable linker. In further synthesis cycles the hydroxyl group is created by cleavage of the protective group from the growing oligomer. This results in formation of a phosphorous acid triester which is reacted with azides. By selecting suitable monomers for the synthesis which have a defined stereoconformation compounds of Formula 1 are produced in a stereocontrolled manner. 

Directed synthesis of oligophosphoramidate stereoisomers

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Kulmbach, Germany

Wilma Thuer