ABSTRACT
This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Isoxazoles/chemistry , Isoxazoles/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular ConformationABSTRACT
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.
Subject(s)
Antiviral Agents/chemistry , Cyclosporine/chemistry , Hepacivirus/physiology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cyclization , Cyclosporine/chemical synthesis , Cyclosporine/pharmacology , Dipeptides/chemical synthesis , Dipeptides/chemistry , Drug Design , Quinidine/chemistry , Stereoisomerism , Virus Replication/drug effectsABSTRACT
Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cyclophilins/antagonists & inhibitors , Cyclosporins/pharmacology , Organic Anion Transporters/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Peptidyl-Prolyl Isomerase F , Cyclophilins/chemistry , Cyclophilins/metabolism , Cyclosporine/chemistry , Cyclosporine/pharmacology , Cyclosporins/chemistry , Dogs , Hepacivirus/drug effects , Hepatitis C/drug therapy , Humans , Hydrophobic and Hydrophilic Interactions , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Liver-Specific Organic Anion Transporter 1 , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Rats , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Synthesis and SAR of 2-alkyloxazoles as class III phosphatidylinositol-4-kinase beta (PI4KIIIß) inhibitors is described. These compounds demonstrate that inhibition of PI4KIIIß leads to potent inhibition of HCV replication as observed in genotype (GT) 1a and 1b replicon and GT2a JFH1 virus assays in vitro.
Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/drug effects , Oxazoles/pharmacology , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Virus Replication/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Hepacivirus/enzymology , Humans , Microbial Sensitivity Tests , Molecular Structure , Oxazoles/chemical synthesis , Oxazoles/chemistry , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The first multiple-site activation of alkynes with amine/halogen functionalities has been established. The reaction was performed by treating alkyne with N,N-dichlorobenzenesulfonamide at 80 degrees C in the presence of palladium acetate catalyst. A new mechanism was proposed which involves the novel formation of beta-halovinyl palladium and pi-allylpalladium species. Excellent regio- and stereoselectivities were achieved with the absolute structure determined by X-ray structural analysis.
