Vanderbilt University

Lieber Institute, Inc.

Merck Sharp + Dohme Corp.

Sirna Therapeutics, Inc.

The Johns Hopkins University

Michael Steven Poslusney

Craig William Lindsley

P Jeffrey Conn

Michael R Wood

Bruce J Melancon

James C Barrow

James C Tarr

Corey R Hopkins

Yifang Huang

Glen E Ernst

Darren W Engers

Weimin Wang

Rubina G Parmar

Peter J Manley

Scott E Wolkenberg

Zhijian Zhao

James J Mulhearn

Kausik K Nanda

James M Salovich

Scott T Harrison

Nathan R Kett

Marina Busuek

J Michael Williams

Amy Zartman

Jeffrey W Schubert

Pankaj Jay Pasricha

B Wesley Trotter

Dominique Swinnen

Wesley B Trotter

Sabine Defays

Ingrid Buchler

Pablo De León

Florian Montel

Pyridine carboxamide compounds for inhibiting NaV1.8 and methods for treating a condition, disease, or disorder associated with an increased NaV1.8 activity or expression are disclosed.

Pyridine carboxamide compounds for inhibiting NAV1.8

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof, or an N-oxide thereof) of formula (I), which are positive allosteric modulators of one or more GABA-A receptors, e.g., which are peripherally restricted, positive allosteric modulators of one or more GABA-A receptors; e.g., which are positive allosteric modulators of one or more GABA-A receptors and which selectively target the peripheral nervous system and organs of the body, and which do not substantially pass through the blood-brain barrier. Said compounds are useful e.g., for the treatment of systemic diseases of the body, e.g., diseases in which modulation of one or more peripherally restricted GABA-A receptors is beneficial (e.g., diseases or disorders which are mediated by GABA-A neuronal activity. This disclosure also features pharmaceutical compositions containing the chemical entities described herein as well as methods of using same for the treatment of systemic diseases of the body.

Substituted benzopyrazolo[1,5-a][1,4]diazepines as GABA positive allosteric modulators

Pyridazine compounds for inhibiting NaV1.8 and methods for treating a condition, disease, or disorder associated with an increased NaV1.8 activity or expression are disclosed.

Pyridazine compounds for inhibiting Nav1.8

Compounds that inhibit COMT enzyme and pharmaceutical compositions comprising the same are provided herein. Methods of treating various psychiatric and neurological disorders with the compounds and pharmaceutical compositions described herein are also provided.

COMT inhibiting methods and compositions

In one aspect, the invention relates to substituted 2-(4-heterocyclylbenzyl)isoindolin-1-one analogs compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M(mAChR M); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Substituted 2-(4-heterocyclylbenzyl)isoindolin-1-one analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M1

In one aspect, the invention relates to substituted 5-aminothieno[2,3-c]pyridazine-6-carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M(mAChR M); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Substituted 5-aminothieno[2,3-C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4

In one aspect, the invention relates to substituted 5-aminothieno[2,3-c]pyridazine-6-carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Substituted thieno[2,3-C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4

In one aspect, the invention relates to substituted 5-aminothieno[2,3-c]pyridazine-6 -carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M(mAChR M); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Substituted 5-aminothieno[2,3&#x2014;C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4

The present invention provides membrane lytic poly(amido amine) polymers, polyconjugates, compositions and methods for the delivery of oligonucleotides for therapeutic purposes.

Membrane lytic poly(amido amine) polymers for the delivery of oligonucleotides

The present invention relates to 4-pyridinone compounds which are inhibitors of catechol O-methyltransferase (COMT), and are useful in the treatment and prevention of neurological and psychiatric disorders and diseases in which COMT enzyme is involved. The present invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which COMT is involved.

Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders

In one aspect, the invention relates to substituted benzylspiroindolin-2-one analogs compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M(mAChR M); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Substituted benzylspiroindolin-2-one analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M1

In one aspect, the invention relates to substituted 1-benzylindolin-2-one analog compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M(mAChR M); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Substituted 1-benzylindolin-2-one analogs as positive allosteric modulators of muscarinic acetylcholine M1 receptors

In one aspect, the invention relates to substituted 4-(1H-pyrazol-4-yl)benzyl analogs compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M(mAChR M); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

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Nashville, TN, United States of America

Michael Steven Poslusney