ABSTRACT
Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Genotype , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Animals , Antiviral Agents/metabolism , Dogs , Humans , Mice , Rats , Rats, Wistar , Viral Nonstructural Proteins/metabolism , Virus Replication/physiologyABSTRACT
Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(V600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(V600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
ABSTRACT
A potent series of inhibitors against the B-Raf(V600E) kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen.
Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sulfonamides/chemistry , Administration, Oral , Amino Acid Substitution , Animals , Binding Sites , Catalytic Domain , Fluorine/chemistry , Microsomes, Liver/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Rats , Structure-Activity RelationshipABSTRACT
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Thiazoles/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Haplorhini , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Viral Nonstructural Proteins/metabolismABSTRACT
The scope of Pd-catalyzed synthesis of N-Boc-protected anilines from aryl bromides and commercially available tert-butyl carbamate is described. For the first time, this process can be conducted at room temperature (17-22 degrees C) using a combination of Pd(2)dba(3).CHCl(3) and a monodentate ligand, tert-butyl X-Phos. Use of sodium tert-butoxide is crucial to the success of the reaction, which proceeds in 43-83% yield.
Subject(s)
Aniline Compounds/chemical synthesis , Bromobenzenes/chemistry , Carbamates/chemistry , Catalysis , Organometallic Compounds/chemistry , Palladium/chemistry , TemperatureABSTRACT
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.
Subject(s)
Antiviral Agents/chemistry , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Hepacivirus/drug effects , Quinolines/chemistry , Quinolones/chemistry , Thiazines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Computer Simulation , Crystallography, X-Ray , DNA-Directed RNA Polymerases/metabolism , Dogs , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Quinolones/chemical synthesis , Quinolones/pharmacology , Rats , Structure-Activity Relationship , Thiazines/chemical synthesis , Thiazines/pharmacology , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and PLK3 was also obtained through these modifications.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Thiophenes/chemistry , Cell Cycle , Cell Cycle Proteins/chemistry , Cell Line, Tumor , Drug Design , Humans , Inhibitory Concentration 50 , Mitosis , Models, Chemical , Molecular Conformation , Protein Binding , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/chemistry , Proto-Oncogene Proteins/chemistry , Solubility , Tumor Suppressor Proteins , Polo-Like Kinase 1ABSTRACT
A 15-member library of phosphaadamantane ligands has been prepared via P-arylation of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phosphaadamantane. Screening of this tertiary phosphine collection has allowed for the rapid determination of the most suitable ligand, specifically 1,3,5,7-tetramethyl-6-(2,4-dimethoxyphenyl)-2,4,8-trioxa-6-phosphaadamantane, for facilitating Suzuki-type couplings of alkyl halides or tosylates containing beta-hydrogens with either boronic acids or alkylboranes.
ABSTRACT
Palladium complexes of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane were prepared and characterized with Pd[1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane](2).dba shown to be an effective catalyst for use in the Suzuki and Sonogashira reactions and the alpha-arylation of ketones. Couplings using this versatile complex proceeded in excellent yields under mild conditions.
ABSTRACT
[reaction: see text] A new class of sterically hindered phosphines based on a phospha-adamantane framework is described. Arylation or alkylation of the 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phospha-adamantane system allows for the preparation of tertiary phosphines suitable for use in palladium-catalyzed cross-coupling reactions. For example, use of a catalytic system incorporating Pd(2)(dba)(3) and 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phospha-adamantane is shown to promote the Suzuki cross-coupling of aryl iodides, bromides, and activated chlorides with a variety of aryl boronic acids at room temperature in a few hours with high yields.
ABSTRACT
The Suzuki cross-coupling of aryl boronic acids with aryl halides, including aryl chlorides, proceeds in the phosphonium salt ionic liquid tetradecyltrihexylphosphonium chloride under mild conditions.
