Leland Stanford Junior University

Siteone Therapeutics, Inc.

Justin Du Bois

John Mulcahy

George P Miljanich

Hassan Pajouhesh

Grant Masaaki Shibuya

Anton Delwig

Brian M Andresen

Jacob Beckley

David C Yeomans

Sandip Biswal

Frederic Menard

James Ross Walker

Andrew William Patterson

Jeffrey E Merit

Anna K Koster

Matthew M Logan

Merritt C Maduke

Tatsuya Toma

Matthew Axtman

Abigail Sloan Devlin

Brian Andresen

Provided herein are compounds, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in treating conditions associated with voltage-gated sodium channel function where the compounds are 11,13-modified saxitoxins according to Formula (I): where R, R, R, R, and Xare as described herein.

11,13-modified saxitoxins for the treatment of pain

Provided herein are compounds, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in treating conditions associated with voltage-gated sodium channel function where the compounds are 11,13-modified saxitoxins according to Formula (I): where R, X, and Xare as described herein. 

Provided herein are compounds, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in treating conditions associated with voltage-gated sodium channel function where the compounds are 11,13-modified saxitoxins according to Formula (I): where R, R, R, R, and Xare as described herein. 

Provided herein are small-molecules for use in modulating chloride ion channel (CLC) activity, particularly the activity of CLC-2, to elucidate the role of CLC-2 in disorders associated with CLC-2 malfunction, and to identify therapeutic leads for their treatment. Compositions and methods for modulating CLC activity are also provided. In certain aspects, the subject compounds and compositions are useful for imaging or channel pull-down studies.

Compositions and methods to modulate chloride ion channel activity

Saxitoxin analogue compounds, compositions, pharmaceutical compositions, methods of synthesis of saxitoxin analogues, methods of imaging, methods of treatment, including methods of treating pain, are provided. Saxitoxin (STX), gonyautoxin (GTX), and zetekitoxin, and variant STX compounds bind to sodium channels and are effective to reduce or block flow of sodium ions through such channels. Such channel block affects nerve and muscle action, and may be effective to reduce or block pain sensations, relax muscles, reduce muscle spasm, and reduce wrinkles. STX analogue binding to sodium channels may also be useful to locate, image, or mark sodium channels, and so be useful in studying sodium channels and sodium channel disorders, and in the diagnosis and treatment of patients suffering from sodium channel disorders. In embodiments, the variant STX compounds include conjugates having increased serum half-life as compared to STX when administered to a subject. Also provided are methods for alleviating pain in a subject in need of treatment.

Methods and compositions for studying, imaging, and treating pain

Provided herein are compounds, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in treating conditions associated with voltage-gated sodium channel function where the compounds are 11,13-modified saxitoxins according to Formula (I): where R, Xand Xare as described herein.

Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in treating conditions associated with voltage-gated sodium channel function, for example conditions associated with pain. The compounds are 10',11&#x2032;-modified saxitoxins. The compounds are optionally additionally modified at carbon 13. In certain embodiments, the 10&#x2032;,11&#x2032;-modified saxitoxins are of Formula I: where R, Rand Rare as described herein. Also provided herein are methods of treating pain in a mammal comprising administering an effective treatment amount of a 10&#x2032;,11&#x2032; modified saxitoxin or composition to a mammal. In an embodiment, the mammal is a human. 

10',11&#x2032;-modified saxitoxins useful for the treatment of pain

Saxitoxin analog compounds, compositions, pharmaceutical compositions, methods of synthesis of saxitoxin analogs, methods of imaging, methods of treatment, including methods of treating pain, are provided. Saxitoxin (STX), gonyautoxin (GTX), and zetekitoxin, and variant STX compounds bind to sodium channels and are effective to reduce or block flow of sodium ions through such channels. Such channel block affects nerve and muscle action, and may be effective to reduce or block pain sensations, relax muscles, reduce muscle spasm, and reduce wrinkles. STX analog binding to sodium channels may also be useful to locate, image, or mark sodium channels, and so be useful in studying sodium channels and sodium channel disorders, and in the diagnosis and treatment of patients suffering from sodium channel disorders. In embodiments, the variant STX compounds include conjugates having increased serum half-life as compared to STX when administered to a subject. In embodiments, the present disclosure provides a method for alleviating pain in a subject in need of treatment, the method comprising administering to the subject an effective amount of a saxitoxin analog compound, or a pharmaceutically acceptable salt, isomer, tautomer or prodrug thereof, whereby pain in said subject is alleviated.

Compounds relating to batrachotoxin are provided, in particular analogs that modulate the activity of sodium channels. Also provided are pharmaceutical compositions comprising compounds of the invention and a pharmaceutically acceptable carrier, including vehicles that modulate transdermal permeation of the compound. The subject compounds are useful in treatments, including treatments to reduce neuronal activity or to bring about muscular relaxation. The compounds also find use in the treatment of subjects suffering from a voltage-gated sodium channel-enhanced ailment or from pain. Further methods are provided for the preparation of the batrachotoxin-related compounds.

Batrachotoxin analogues, compositions, uses, and preparation thereof

Compound derivatives of aconitine are provided, in particular derivatives that modulate the activity of sodium channels. Also provided are pharmaceutical compositions comprising compounds of the invention and a pharmaceutically acceptable carrier. The subject compounds are useful in treatments, including treatments to modulate neuronal activity or to bring about muscular relaxation. The compounds also find use in the treatment of subjects suffering from a voltage-gated sodium channel-enhanced ailment or from pain. Further methods are provided for the preparation of the aconitine derivatives.

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Menlo Park, CA, United States of America

Justin Du Bois