ABSTRACT
γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aß42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aß42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described.
Subject(s)
Alzheimer Disease/drug therapy , Amides/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Picolines/pharmacology , Alzheimer Disease/enzymology , Amides/chemistry , Animals , HEK293 Cells , Humans , Picolines/chemistry , Rats , Rats, Sprague-DawleyABSTRACT
Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Binding Sites , Biological Availability , Cell Membrane Permeability , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Models, Molecular , Molecular Structure , Solubility , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
[reaction: see text] CuI-catalyzed N-arylation of imidazoles with aryl bromides has been achieved in a near-homogeneous system that utilizes tetraethylammonium carbonate as base, 8-hydroxyquinoline as ligand, and H2O as cosolvent. Preliminary results with aryl chlorides are also reported.