ABSTRACT
[15 N]-Cholamine is an isotope tag for metabolomics research, because it possesses 2 important properties: an NMR active isotope and a permanent charge for MS sensitivity. Here, we present a scalable synthesis of [15 N]-cholamine.
Subject(s)
Nitrogen Isotopes/chemistry , Trimethyl Ammonium Compounds/chemistry , Bromides/chemistry , Carboxylic Acids/chemistry , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methodsABSTRACT
The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.
Subject(s)
Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazines/chemistry , Pyrroles/chemistry , Drug Design , Humans , Janus Kinase 3/metabolism , Models, Molecular , Molecular Conformation , Molecular Structure , Phosphorylation , Piperidines/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.
Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Quinolines/pharmacology , Sulfonamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Dogs , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , Humans , Models, Molecular , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Sulfonamides/chemistry , Sulfonamides/pharmacokineticsABSTRACT
Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists led to the discovery of compounds with increased intrinsic permeability. This effort led to the identification of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile.
Subject(s)
Amides/chemistry , Aza Compounds/pharmacology , CCR5 Receptor Antagonists , Aza Compounds/chemistry , Aza Compounds/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The introduction of N-substituted pyrazoles in a new series of CCR5 antagonists was shown to substantially increase antiviral activity.
Subject(s)
Anti-HIV Agents/chemistry , CCR5 Receptor Antagonists , Pyrazoles/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Humans , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, CCR5/metabolism , Structure-Activity RelationshipABSTRACT
This review will focus on the discovery and clinical development of small molecule antagonists of CCR5 for the treatment of HIV-1/AIDS, as well as for the potential treatment of inflammatory diseases. In particular, we will focus on the specific medicinal chemistry problems that were faced during the discovery of the molecules. We will also describe limited data from clinical development phases focusing on specific issues that arose during the clinical trials. Finally, we will touch on the mechanism of action of CCR5 antagonists.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , CCR5 Receptor Antagonists , Acquired Immunodeficiency Syndrome/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , HIV-1/drug effects , Humans , Molecular WeightABSTRACT
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Subject(s)
Anti-HIV Agents/chemistry , Benzamides/chemistry , CCR5 Receptor Antagonists , HIV Fusion Inhibitors/chemistry , Pyrroles/chemistry , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Benzamides/chemical synthesis , Benzamides/pharmacology , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Rats , Receptors, CCR5/metabolism , Structure-Activity RelationshipABSTRACT
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc.
Subject(s)
Anti-HIV Agents/chemistry , Azabicyclo Compounds/chemistry , CCR5 Receptor Antagonists , Cyclohexanes/chemistry , HIV Fusion Inhibitors/chemistry , Triazoles/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Cell Line, Tumor , Cyclohexanes/chemical synthesis , Cyclohexanes/pharmacology , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/pharmacology , Humans , Maraviroc , Models, Chemical , Receptors, CCR5/metabolism , Triazoles/chemical synthesis , Triazoles/pharmacologyABSTRACT
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the conformationally restricted 4-aminopiperidine ring found in several series of CCR5 antagonists.
Subject(s)
CCR5 Receptor Antagonists , Drug Evaluation, Preclinical , Piperidines/chemistry , Models, MolecularABSTRACT
Replacement of a secondary amide with an N-acyl or N-sulfonyl gem-disubstituted azacyle in a series of CCR5 antagonists led to the identification of compounds with excellent in vitro HIV antiviral activity and increased intrinsic membrane permeability.
Subject(s)
Amides/chemistry , Anti-HIV Agents/chemistry , Aza Compounds/chemistry , CCR5 Receptor Antagonists , HIV Fusion Inhibitors/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Cell Line, Tumor , Cell Membrane Permeability/drug effects , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/pharmacology , Humans , Receptors, CCR5/metabolismABSTRACT
The discovery of a series of quinazolinone-based fungal efflux pump inhibitors by high-throughput screening for potentiation of fluconazole in C. albicans is described. Attempts to improve the aqueous solubility of screening hits led to the discovery of an analog with greatly improved physical properties and activity against clinically-relevant Candida spp.
Subject(s)
ATP-Binding Cassette Transporters/antagonists & inhibitors , Antifungal Agents/chemical synthesis , Candida/drug effects , Fungal Proteins/antagonists & inhibitors , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Piperazines/chemical synthesis , Quinazolines/chemical synthesis , Antifungal Agents/pharmacology , Candida/enzymology , Drug Resistance, Fungal , Drug Synergism , Fluconazole/chemistry , Fluconazole/pharmacology , Humans , In Vitro Techniques , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of Candida albicans and Candida glabrata over-expressing ABC-type efflux pumps are systematically explored.
Subject(s)
Antifungal Agents/chemical synthesis , Candida/drug effects , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Piperazines/chemical synthesis , Quinazolines/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida/enzymology , Candida albicans/drug effects , Candida albicans/enzymology , Candida glabrata/drug effects , Candida glabrata/enzymology , Drug Resistance, Fungal , Drug Synergism , Fluconazole/chemistry , Fluconazole/pharmacology , Fungal Proteins/antagonists & inhibitors , Humans , Microbial Sensitivity Tests , Piperazines/chemistry , Piperazines/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Dihydropacidamycins having an antibacterial spectrum modified from that of the natural product pacidamycins and mureidomycins have been synthesized. Synthetic dihydropacidamycins with noteworthy antibacterial activity against wild-type and resistant Escherichia coli have been identified (MIC=4-8 microg/mL). Some dihydropacidamycins are shown to have activity against multi-resistant clinical strains of Mycobacterium tuberculosis. Compounds of this class are inhibitors of the cell wall biosynthetic enzyme, MraY.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Peptides/chemical synthesis , Peptides/pharmacology , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Gram-Negative Aerobic Bacteria/drug effects , Gram-Negative Aerobic Bacteria/growth & development , HumansABSTRACT
We describe in this paper the synthesis of 1,2-di-O-acetyl-5-azido-3,5-dideoxy-alpha,beta-L-arabinofuranose, a carbohydrate donor that was used for the synthesis of 1-(5'-amino-3',5'-dideoxy-alpha-L-arabinofuranosyl)uracil, the nucleoside found in dihydropacidamycin D. The carbohydrate donor was also used for the synthesis of a set of new nucleosides that were introduced in new dihydropacidamycins. These compounds were tested for biological activity, and the results showed that uracil is the only base recognized by MraY.
