Physico-chemical characterization of some beta blockers and anti-diabetic drugs-potentiometric and spectrophotometric pKa determination in different co-solvents
PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
The identification of a novel class of potent pan-genotypic
NS5A
inhibitors with good pharmacokinetic profile suitable for potential
use in treating HCV infections is disclosed here. The present series
of compounds are with less complex tricyclic central core, identified
through a systematic SAR study carried out on biphenyl moiety. The
SAR outcome has confirmed the requirement of near planar and linear
conformation of the molecule to achieve the best pan-genotypic activity.
In addition, SAR with substituted imidazoles on improvement of antiviral
activity is disclosed. The newly identified compounds 12, 16, 19–21 have shown
desirable pharmacokinetic profiles with a favorable uptake of compounds
in liver and maintained a significant concentration for up to 8 h
in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to
ledipasvir and daclatasvir. Additional characterization and preliminary
safety assessment resulted in the identification of compound 20 as a potential clinical candidate.
The role of calcium release-activated
calcium (CRAC) channels is
well characterized and is of particular importance in T-cell function.
CRAC channels are involved in the pathogenesis of several autoimmune
diseases, making it an attractive therapeutic target for treating
inflammatory diseases, like rheumatoid arthritis (RA). A systematic
structure–activity relationship study with the goal of optimizing
lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity
and a remarkable pharmacokinetic profile. Further characterization
in in vivo RA models and subsequent histopathological evaluation of
tissues led to the identification of 36 as a clinical
candidate. Compound 36 displayed an excellent safety
profile and had a sufficient safety margin to qualify it for use in
human testing. Oral administration of 36 in Phase 1 clinical
study in healthy volunteers established favorable safety, tolerability,
and good target engagement as measured by levels of IL-2 and TNF-α.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.