Advertisement

Topics

Design and identification of a novel, functionally subtype selective GABA positive allosteric modulator (PF-06372865).

08:00 EDT 9th April 2019 | BioPortfolio

Summary of "Design and identification of a novel, functionally subtype selective GABA positive allosteric modulator (PF-06372865)."

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.

Affiliation

Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804
Pages:

Links

DeepDyve research library

PubMed Articles [18471 Associated PubMed Articles listed on BioPortfolio]

Cooperativity of E-prostanoid receptor subtypes in regulating signaling and growth inhibition in human airway smooth muscle.

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...

Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator.

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...

The α2,3-selective potentiator of GABA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats.

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...

Brain GABA levels are reduced in alcoholic liver disease: A proton magnetic resonance spectroscopy study.

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 ...

Identification of Carassius auratus gibelio liver cell proteins interacting with the GABA receptor γ2 subunit using a yeast two-hybrid system.

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...

Clinical Trials [6382 Associated Clinical Trials listed on BioPortfolio]

Impact of GABA-Enhancing Agents on Cortical GABA Concentrations Across the Menstrual Cycle in Women

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...

Effectiveness of GABA Agonists in Reducing the Reinforcing Effects of Cocaine

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...

Cortical GABA Concentrations in Subjects With Primary Insomnia and Depression in Partial Remission With Residual Insomnia

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...

Risk and Clinical Benefit of Chemotherapy and Intensive Endocrine Therapy for Luminal B1 Early-stage Breast Cancer

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...

GABA Mechanisms Underlying the Vulnerability to Alcohol Dependence

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...

Medical and Biotech [MESH] Definitions

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.

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Searches Linking to this Article