Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

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.

QbD-Based UPLC Method for Quantification of Brexpiprazole in Presence of Impurities and Application to In Vitro Dissolution.

Quality-by-design-based UPLC method was developed for chromatographic separation to quantify the antischizophrenic drug brexpiprazole in the presence of impurities. Research findings from pH-scouting studies were used as control variables which influence the chromatographic separation. The peak tailing and resolution are the response variables and established the design-space by DoE-study for selection of suitable chromatographic conditions. Separation was achieved with lower particle size stationary phase and buffer pH 2.0 in the mobile phase. The present method developed through C18 50 × 2.1 mm, Ethylene-Bridged-Hybrid technology column with 1.7 µm particles, mobile phase consists of pH 2.0 buffer and acetonitrile (67:33 v/v), flow rate of 0.5 mL min-1 and detection wavelength at 215 nm. The retention time of brexpiprazole is 0.6 min and all impurities were eluted within 2 min. The method linearity ranges were 20.4-61.3 µg mL-1 for assay and 0.88-6.59 µg mL-1 for dissolution with correlation-coefficients of 0.9999 and 0.9998 for assay and dissolution, respectively. The recovery values were found in between 99.3 and 100.9%. The method shows stability-indicating on the basis of noninterference of placebo, and impurities from forced-degradation studies. Method validation was carried out according to ICH guideline Q2 (R1).