ABSTRACT
Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase , Brain , Multiple Sclerosis , Protein Kinase Inhibitors , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , Multiple Sclerosis/drug therapy , Humans , Animals , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/chemistry , Brain/metabolism , Mice , Drug Discovery , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Rats , Structure-Activity Relationship , Cell Proliferation/drug effects , FemaleABSTRACT
An operationally simple protocol has been discovered that couples primary or secondary amines with N-aryl-substituted lactams to deliver differentiated diamines in moderate to high yields. The process allows for the partial reduction of a lactam in the presence of Cp2ZrHCl (Schwartz's reagent), followed by a reductive amination between the resulting hemiaminal and primary or secondary amine. These reactions can be telescoped in a one-pot fashion to significantly simplify the operation. The scope of amines and substituted lactams of various ring sizes was demonstrated through the formation of a range of differentiated diamine products. Furthermore, this methodology was expanded to include N-aryl pyrrolidinone substrates with an enantiopure ester group at the 5-position, and α-amino piperidinones were prepared with complete retention of stereochemical information. The development of this chemistry has enabled the consideration of lactams as useful synthons.
