Edward Walker

Arylsulfonamide CB2 receptor agonists: SAR and optimization of CB2 selectivity.

A high-throughput screening campaign resulted in the discovery of a highly potent dual cannabinoid receptor 1 (CB1) and 2 (CB2) agonist. Following a thorough SAR exploration, a series of selective CB2 full agonists were identified.

Tropomyosin receptor kinase inhibitors: a patent update 2009 – 2013

Introduction: Tropomyosin receptor kinases (Trks) are a family of three similar tyrosine kinases activated by peptide hormones of the neurotrophin family. The nerve growth factor antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA pathway in pain. As an alternative modality, small-molecule inhibitors of the Trks have been pursued in recent years to probe the role of these neurotrophin pathways in pain, cancer and other indications. Areas covered: This paper reviews the patent literature between mid-2009 and 2013, claiming inhibitors of Trk family members as the primary biological targets. Additional patents have been reviewed where Trk is not the main kinase of interest but in which high Trk potency is observed and the chemical matter is particularly noteworthy. Patents pre-dating this period have been reviewed previously. Scifinder and Google were used to find relevant patents and clinical information using Trk or Tropomyosin as the search term. Expert opinion: Considerable recent progress has been made in the identification of selective pan Trk inhibitors with pharmacodynamic and pharmacokinetic properties appropriate for clinical evaluation. Inhibitors of both active and inactive conformations of the Trks as well as peripherally restricted molecules have been identified. Furthermore, TrkA-selective allosteric inhibitors have recently been disclosed, which enables the biology of this isoform to be probed. The recent identification of a TrkA gene fusion in a subset of lung cancer patients will increase further the attraction of Trk inhibition to the pharmaceutical industry.

1,4-Diazepane compounds as potent and selective CB2 agonists: optimization of metabolic stability.

A high-throughput screening campaign has identified 1,4-diazepane compounds which are potent Cannabinoid receptor 2 agonists with excellent selectivity against the Cannabinoid receptor 1. This class of compounds suffered from low metabolic stability. Following various strategies, compounds with a good stability in liver microsomes and rat PK profile have been identified.

Aryl 1,4-diazepane compounds as potent and selective CB2 agonists: optimization of drug-like properties and target independent parameters.

A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability.