ABSTRACT
Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.
Subject(s)
Protein Kinase Inhibitors/chemistry , Receptor, trkA/antagonists & inhibitors , Allosteric Regulation , Amino Acid Sequence , Animals , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Half-Life , High-Throughput Screening Assays , Humans , Ligands , Microsomes, Liver/metabolism , Molecular Dynamics Simulation , Protein Binding , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Rats , Receptor, trkA/metabolism , Sequence Alignment , Structure-Activity RelationshipABSTRACT
A short synthesis of the homochiral disubstituted butenolide 1 is described in four steps from arabitol. The key steps are the selective kinetic protection of arabitol and the cyclization of 11 to form the butenolide ring. This last transformation represents a rare example of a fully stereoselective cyclitive desymmetrization process of a "pseudo"-C2-symmetric substrate.
