Sanford Burnham Prebys Medical Discovery Institute

Sanford-burnham Medical Research Institute

The Salk Institute for Biological Studies

Merck + Co., Inc.

Brown University

Nicholas David Peter Cosford

Mitchell Dennis Vamos

Douglas J Sheffler

Dhanya Raveendra-Panickar

John Howard Hutchinson

John A T Young

Sumit K Chanda

John M Marlett

Peter Teriete

Reto Andreas Gadient

Arturo Diaz

Lars Pache

Ian A McDonald

Jean-Michel Andre Vernier

Edwin J Schweiger

Dhanya Raveendra Panickar

Rowena Villanueva Cube

Carolina L Haass-Koffler

Leo Solomon Bleicher

John At Young

John AT Young

John Marlett

Stress responses involve corticotropin releasing factor (CRF), the two cognate receptors (CRFand CRF) and the CRF-binding protein (CRFBP). Utilizing a novel cell-based assay, a C-terminal CRFBP fragment [CRFBP(10 kD)] was found to potentiates CRF-intracellular Carelease, demonstrating that CRFBP possesses excitatory roles in addition to the inhibitory role established by the N-terminal fragment of CRFBP [CRFBP(27 kD)]. This interaction was CRF-specific, as CRFresponses were not potentiated by CRFBP(10 kD). As there were currently no small molecule ligands available that selectively interact with either CRFBP or CRF, a cell-based assay was miniaturized, wherein CRFBP(10 kD) was fused as a chimera with CRF, that allowed us to a perform a high-throughput screen (HTS) of approximately 350,000 small molecules. This resulted in the identification of negative allosteric modulators (NAMs) of the CRFBP(10 kD)-CRFcomplex that blunt CRF-induced potentiation of N-Methyl-D-aspartic acid receptor (NMDAR)-mediated synaptic transmission in dopamine neurons in the ventral tegmental area (VTA). These results provide the first evidence of specific roles for CRFand CRFBP in the modulation of neuronal activity and suggest that NMDARs in the VTA may be a target for the treatment of stress and substance abuse disorders such as alcohol use disorder.

Compositions and methods for the modulation of the corticotropin releasing factor binding protein and the treatment of alcohol use disorder

Provided herein are compounds that modulate the activity of inhibitor of apoptosis proteins (IAPs), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

Inhibitor of apoptosis protein (IAP) antagonists

Provided herein are small molecule active metabotropic glutamate subtype-2 and -3 receptor negative allosteric modulators (NAMs), compositions comprising the compounds, and methods of using the compounds and compositions.

Metabotropic glutamate receptor negative allosteric modulators (NAMs) and uses thereof

Provided herein is the use of compounds that modulate the activity of inhibitor of apoptosis proteins (IAPs), alone or in combination with other therapeutic agents, in the treatment of human immunodeficiency virus (HIV).

Use of inhibitor of apoptosis protein (IAP) antagonists in HIV therapy

Provided herein is the use of compounds that modulate the activity of inhibitor of apoptosis proteins (IAPs), alone or in combination with other therapeutic agents, in the treatment of human immunodeficiency virus (HIV). Described herein is the use of IAP antagonists in the treatment of human immunodeficiency virus (HIV) in a mammal, alone or in combination with other therapeutic agents used in HIV therapy. In one aspect, provided herein is a method of treating human immunodeficiency virus (HIV) in an individual in need thereof comprising administering a therapeutically effective amount of at least one inhibitor of apoptosis proteins (IAP) antagonist.

Provided herein are compounds that modulate the activity of inhibitor of apoptosis proteins (IAPB), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

Metabotropic glutamate receptor negative allosteric modulators (NAMS) and uses thereof

In accordance with the present invention, there is provided a novel class of heterocyclic compounds. Compounds of the invention contain a substituted, unsaturated five, six or seven membered heterocyclic ring that includes at least one nitrogen atom and at least one carbon atom. The ring additionally includes three, four or five atoms independently selected from carbon, nitrogen, sulfur and oxygen atoms. The heterocyclic ring has at least one substituent located at a ring position adjacent to a ring nitrogen atom. This mandatory substituent of the ring includes a moiety (B), linked to the heterocyclic ring via a carbon-carbon double bond, a carbon-carbon triple bond or an azo group. The mandatory substituent is positioned adjacent to the ring nitrogen atom. Invention compounds are capable of a wide variety of uses. For example heterocyclic compounds can act to modulate physiological processes by functioning as agonists and antagonists of receptors in the nervous system. Invention compounds may also act as insecticides, and as fungicides. Pharmaceutical compositions containing invention compounds also have wide utility.

Thiazolyl(pyridyl)ethyne compounds

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La Jolla, CA, United States of America

Nicholas David Peter Cosford