Discovery and pre-clinical characterization of a selective PI3Kδ inhibitor, LL-00071210 in rheumatoid arthritis.

PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kß as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with ∼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.

Technologies and strategies to characterize and quantitate metabolites in drug discovery and development.

Pharmacokinetics and toxicokinetics studies rely on the quantitation of drugs and its metabolites. Drug metabolism studies are based on the characterization of the structure of drugs and their metabolites. Liquid chromatography coupled with mass spectrometry is an undisputed technology for the routine analysis of drugs and metabolites in the drug discovery set-up. Advancements in liquid chromatography and mass spectrometry have accelerated and improved drug discovery and development. Identification and quantitation of drugs and metabolites have gained importance because of their relevance to clinical research. In the present review, we present a bird's eye view of qualitative and quantitative analysis of drugs and their metabolites. Various technologies available to characterize and quantitate metabolites are analyzed. Characterization of metabolites of the sulfonyl urea drug glyburide and the kinetics of glyburide metabolism are discussed in detail.