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
The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.
Subject(s)
Isoquinolines/pharmacology , Isoquinolines/pharmacokinetics , MAP Kinase Signaling System/drug effects , Mutant Proteins/antagonists & inhibitors , Mutation , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cell Line, Tumor , Drug Discovery , Humans , Isoquinolines/administration & dosage , Isoquinolines/chemical synthesis , Male , Mice , Models, Molecular , Molecular Conformation , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Rats , Substrate SpecificityABSTRACT
A series of substituted 4-anilino-7-phenyl-3-quinolinecarbonitriles has been prepared as Src kinase inhibitors. Optimal activity is observed with compounds that have basic amines attached via the para position of the 7-phenyl ring, and a hydrogen atom at the C-6 position. The best compounds are low nanomolar inhibitors of Src kinase, and have potent activity against Src-transformed fibroblast cells.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nitriles/chemical synthesis , Nitriles/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , src-Family Kinases/antagonists & inhibitors , Indicators and Reagents , Structure-Activity RelationshipABSTRACT
A series of 8-anilinoimidazo[4,5-g]quinoline-7-carbonitriles was synthesized and evaluated as Src kinase inhibitors. Several aniline substituents were surveyed, as well as water-solubilizing groups at the C-2 and N-3 positions. Potent Src inhibitors were identified, with N-3 providing the best position for an additional water-solubilizing group.