ABSTRACT
Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (13), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.
Subject(s)
Arthritis, Rheumatoid , Autoimmune Diseases , Lupus Erythematosus, Systemic , Humans , Agammaglobulinaemia Tyrosine Kinase , Protein Kinase Inhibitors/therapeutic use , Arthritis, Rheumatoid/drug therapy , Autoimmune Diseases/drug therapy , Lupus Erythematosus, Systemic/drug therapyABSTRACT
Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.
ABSTRACT
A series of androgen receptor modulators based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.
Subject(s)
Oxazines/chemical synthesis , Oxazines/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Receptors, Androgen/drug effects , Animals , Cell Line , Dose-Response Relationship, Drug , Humans , Indicators and Reagents , Male , Models, Molecular , Orchiectomy , Rats , Receptors, Androgen/chemistry , Receptors, Progesterone/chemistry , Receptors, Progesterone/drug effects , Receptors, Somatotropin/chemistry , Receptors, Somatotropin/drug effects , Structure-Activity Relationship , Testosterone/bloodABSTRACT
A series of 5-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes was synthesized and profiled for their ability to act as selective glucocorticoid receptor modulators (SGRMs). The synthesis and structure-activity relationships for this series of compounds are presented.
