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The design, optimization and evaluation of a series of novel imidazopyridazine-based subtype-selective positive allosteric modulators (PAMs) for the GABA ligand-gated ion channel are described. From a set of initial hits multiple subseries were designed and evaluated based on binding affinity and functional activity. As designing in the desired level of functional selectivity proved difficult, a probability-based assessment was performed to focus the project's efforts on a single subseries which had the greatest odds of delivering the target profile. These efforts ultimately led to the identification of two pre-candidates from this subseries, which were advanced to pre-clinical safety studies and subsequently to the identification of the clinical candidate PF-06372865.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Prostaglandin E2 (PGE) is produced in the airway during allergic lung inflammation and both promotes and inhibits features of asthma pathology. These mixed effects relate to 4 E-prostanoid (EP) recept...
The objective of this phase 2a study was to assess the activity of PF-06372865, a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABA receptors with minimal activity at α1-containi...
Clinical evidence indicates that positive allosteric modulators (PAMs) of GABA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABA receptor PAMs...
Baclofen, a selective γ-aminobutyric acid (GABA) receptor agonist, has emerged as a potential treatment for alcohol use disorder with much unexplained variation in response to treatment efficacy and ...
The γ-aminobutyric acid type A (GABA) receptor is an important pentameric inhibitory neurotransmitter receptor, and the γ2 subunit of this receptor plays a key role in potentiation of the GABA respo...
The goal of this series of challenge studies is to examine the impact of menstrual cycle phase on cortical GABA response to administration of agents with either direct (benzodiazepines) or...
Cocaine abuse continues to represent a significant public-health concern. Cocaine likely creates its addictive effects by increasing levels of dopamine, a chemical found in the brain. GABA...
Disturbances in the amino acid neurotransmitter (AANt), gamma-amino butyric acid (GABA) function are hypothesized to contribute to the neurobiology of Major Depressive Disorder (MDD) and i...
Breast cancer is the most common female malignancy in the world, and the leading cause of cancer-associated mortalities among women. Hormone receptors (HR) including ER and PR are the main...
This Project will explore the hypothesis that individuals with a family history positive for alcohol dependence (without any current Axis I disorder, except nicotine dependence), experienc...
Drugs that bind to but do not activate GABA-B RECEPTORS thereby blocking the actions of endogenous or exogenous GABA-B RECEPTOR AGONISTS.
Drugs that bind to but do not activate GABA-A RECEPTORS thereby blocking the actions of endogenous or exogenous GABA-A RECEPTOR AGONISTS.
An approach, process, or methodology which emphasizes credible evidence and the best available scientific knowledge, judiciously integrated to achieve the best possible outcomes in structural design. For example, the design of a new OUTPATIENT CLINIC might incorporate a review of published research on outpatient clinic design, decisions on similar past projects, along with interviews with staff and consumers.
Endogenous compounds and drugs that bind to and activate GABA-A RECEPTORS.
Endogenous compounds and drugs that bind to and activate GABA-B RECEPTORS.