In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.
BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties.
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridazines/chemistry , Pyridazines/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , Agammaglobulinaemia Tyrosine Kinase , Animals , Dogs , Humans , Mice , Microsomes, Liver/metabolism , Models, Molecular , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Protein-Tyrosine Kinases/metabolism , Pyridazines/metabolism , Pyridazines/pharmacokinetics , Pyrimidinones/metabolism , Pyrimidinones/pharmacokinetics , Rats , Thiophenes/metabolism , Thiophenes/pharmacokinetics
SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors.
Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidinones/chemistry , Thiophenes/chemistry , Agammaglobulinaemia Tyrosine Kinase , Animals , Benzamides/chemistry , Benzamides/metabolism , Binding Sites , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Crystallography, X-Ray , Dogs , Half-Life , Humans , Mice , Microsomes, Liver/metabolism , Molecular Dynamics Simulation , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Rats , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacokinetics
Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications.
Indazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/pharmacology , Spleen/drug effects , Administration, Oral , Animals , Cells, Cultured , Drug Discovery , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Magnetic Resonance Spectroscopy , Mice , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrazines/administration & dosage , Pyrazines/chemistry , Rats , Spectrometry, Mass, Electrospray Ionization , Spleen/enzymology , Structure-Activity Relationship
There has been an increasing call for and development of culturally appropriate substance prevention/intervention for ethnic minorities in schools and communities, especially among reservation and in urban American Indian and Alaska Native (AIAN) communities. Past attempts to intervene in and reduce misuse of alcohol and other drugs have not had great success. The Journeys of the Circle Project utilized innovative programs with a strong emphasis on historic cultural traditions.
Adaptation, Psychological , Alcohol Drinking/ethnology , Alcohol Drinking/prevention & control , Indians, North American , Adolescent , Humans , Risk Factors , United States
