ABSTRACT
A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.
Subject(s)
Fluorine/chemistry , Fluorine/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolism , Agammaglobulinaemia Tyrosine Kinase , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Protein Conformation , Structure-Activity RelationshipABSTRACT
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Isoquinolines/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase , Crystallography, X-Ray , Drug Design , Humans , Isoquinolines/chemistry , Isoquinolines/metabolism , Models, Chemical , Models, Molecular , Molecular Structure , Protein Binding , Protein Structure, Secondary , Protein Structure, Tertiary , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolismABSTRACT
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
Subject(s)
Drug Discovery/methods , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyridones/pharmacology , Pyridones/pharmacokinetics , Pyrimidines/pharmacology , Pyrimidines/pharmacokinetics , Administration, Oral , Arthritis, Rheumatoid/drug therapy , Biological Availability , Cell Line , Clinical Trials as Topic , Humans , Mitogen-Activated Protein Kinase 14/chemistry , Models, Molecular , Protein Conformation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyridones/administration & dosage , Pyridones/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.
