Arbutus Biopharma Corporation

Tekmira Pharmaceuticals Corporation

The University of British Columbia

Dermira (canada), Inc.

Alnylam Pharmaceuticals, Inc.

Valocor Therapeutics, Inc.

Dirmira (canada), Inc.

Jianxin Chen

Kallanthottathil G Rajeev

Muthusamy Jayaraman

Muthiah Manoharan

Steven Ansell

Laxman Eltepu

Zaihui Zhang

Serguei Sviridov

Xinyao Du

Timothy Scott Daynard

Shisen Wang

Gregory B Chopiuk

Jun Yan

Akin Akinc

Jayaprakash K Narayanannair

Joseph Robert Dorkin

Xiaojun Qin

William Cantley

Pieter Rutter Cullis

Michael J Hope

Thomas D Madden

Marco A Ciufolini

Sean C Semple

Barbara Low Shoud Mui

Steven Michial Ansell

Joseph R Dorkin

Muthiah Mancharan

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure wherein:

Lipids and compositions for the delivery of therapeutics

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention formula (I) provides lipids having the following structure XXXIII wherein: Rand Rare each independently for each occurrence optionally substituted C-Calkyl, optionally substituted C-Calkenyl, optionally substituted C-Calkynyl, optionally substituted C-Cacyl, or -linker-ligand; Ris H, optionally substituted C-Calkyl, optionally substituted C-Calkenyl, optionally substituted C-Calkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, &#x3c9;-aminoalkyls, &#x3c9;-(substituted)aminoalkyls, &#x3c9;-phosphoalkyls, &#x3c9;-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure XXXIII, wherein:Rand Rare each independently for each occurrence optionally substituted C-Calkyl, optionally substituted C-Calkenyl, optionally substituted C-Calkynyl, optionally substituted C-Cacyl, or -linker-ligand; Ris H, optionally substituted C-Calkyl, optionally substituted C-Calkenyl, optionally substituted C-Calkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, &#x3c9;-aminoalkyls, &#x3c9;-(substituted)aminoalkyls, &#x3c9;-phosphoalkyls, &#x3c9;-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

The present invention provides superior compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of specific target proteins at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.

Amino lipids and methods for the delivery of nucleic acids

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure wherein:Rand Rare each independently for each occurrence optionally substituted C-Calkyl, optionally substituted C-Calkenyl, optionally substituted C-Calkynyl, optionally substituted C-Cacyl, or -linker-ligand; Ris H, optionally substituted C-Calkyl, optionally substituted C-Calkenyl, optionally substituted C-Calkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, &#x3c9;-aminoalkyls, &#x3c9;-(substituted)aminoalkyls, &#x3c9;-phosphoalkyls, &#x3c9;-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40 K), optionally substituted mPEG (mw 120-40 K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

Topical formulations and method of using the same are provided. The topical formulation comprises a pyrazolylbenzothiazole derivative of the following formula (1) wherein X, R, R, Rand Rare described herein.

Pyrazolylbenzothiazole derivatives and their use as therapeutic agents

The invention features a cationic lipid of formula I,  Also disclosed are targeting lipids, and specific lipid formulations comprising such targeting lipids.

Lipid formulations

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention formula (I) provides lipids having the following structure XXXIII wherein: Rand Rare each independently for each occurrence optionally substituted C-Calkyl, optionally substituted C-Calkenyl, optionally substituted C-Calkynyl, optionally substituted C-Cacyl, or -linker-ligand; Ris H, optionally substituted C-Calkyl, optionally substituted C-Calkenyl, optionally substituted C-Calkynyl, alky lhetro cycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, &#x3c9;-aminoalkyls, &#x3c9;-(substituted)aminoalkyls, &#x3c9;-phosphoalkyls, &#x3c9;-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O). 

Lipid formulation

Pharmaceutical compositions and compounds are provided. The compounds of the invention have use as therapeutic agents, e.g., they demonstrate anti-proliferative, anti-inflammatory, anti-angiogenic, anti-migration activities. In one embodiment of the invention, formulations of the compounds in combination with a physiologically acceptable carrier are provided. The pharmaceutical formulations are useful in the treatment of, e.g., anti-inflammatory, renal, and hyperproliferative disorders. The compounds of the invention are pyrazolylbenzothiazole derivatives of the following formula (1) wherein X, R, R, Rand Rare described herein.

Pharmaceutical pyrazolybenzothiazole compositions of formula (1) are provided. The compositions may be pharmaceutically acceptable salts. R, Rand Rat each occurrence are independently selected from amino, aminosulfinyl, aminosulfonyl, aryl, azido, halogen, heteroalkyl, heteroaryl, hydrazinyl, hydrocarbyl, hydrogen, hydroxyl, nitro, nitroso, phosphate, phosphinate, phosphonate, phosphonium, phosphorothioate, phosphoryl, sulfamoyl, sulfate, sulfinic acid, sulfonamido, sulfonate, sulfonic acid, sulfonyl, sulfoxido, thiol, thioureido, and ureido, and Ris selected from hydrogen, heteroalkyl, heteroaryl, and hydrocarbyl. 

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Cambridge, MA, United States of America

Jianxin Chen