ABSTRACT
The structure based drug design, synthesis and structure-activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.
Subject(s)
Benzamides/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Triazoles/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Benzamides/chemical synthesis , Benzamides/pharmacology , Binding Sites , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Crystallography, X-Ray , Drug Design , Humans , Microsomes, Liver/metabolism , Models, Chemical , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The copper-catalyzed hydroboration of benzylidenecyclopropanes, conveniently accessed in one step from readily available benzaldehydes, is reported. Under otherwise identical reaction conditions, two distinct phosphine ligands grant access to different products by either suppressing or promoting cyclopropane opening via ß-carbon elimination. Computational studies provide insight into how the rigidity and steric environment of these different bis-phosphine ligands influence the relative activation energies of ß-carbon elimination versus protodecupration from the key benzylcopper intermediate. The method tolerates a wide variety of heterocycles prevalent in clinical and pre-clinical drug development, giving access to valuable synthetic intermediates. The versatility of the tertiary cyclopropylboronic ester products is demonstrated through several derivatization reactions.
ABSTRACT
Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.
Subject(s)
Drug Discovery , Pain/drug therapy , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Humans , Ligands , Molecular Docking Simulation , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyridines/therapeutic use , Rats , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Solubility , Structure-Activity Relationship , Tissue DistributionABSTRACT
The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.