ABSTRACT
The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.
Subject(s)
Anti-HIV Agents/pharmacology , Drug Discovery , Drug Resistance, Viral/drug effects , HIV-1/drug effects , Pyridones/chemistry , Pyridones/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Cells, Cultured , Crystallography, X-Ray , Dogs , HIV-1/genetics , Humans , Inhibitory Concentration 50 , Molecular Structure , Mutation , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Inhibitors/chemistryABSTRACT
Next generation NNRTIs are sought which possess both broad spectrum antiviral activity against key mutant strains and a high genetic barrier to the selection of new mutant viral strains. Pyridones were evaluated as an acyclic conformational constraint to replace the aryl ether core of MK-4965 (1) and the more rigid indazole constraint of MK-6186 (2). The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTI's.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , Pyridones/chemistry , Reverse Transcriptase Inhibitors/chemical synthesis , Binding Sites , Cell Line , Computer Simulation , Drug Design , Enzyme Activation/drug effects , HIV/enzymology , HIV Reverse Transcriptase/metabolism , Humans , Protein Structure, Tertiary , Pyrazoles/chemistry , Pyridines/chemistry , Pyridones/chemical synthesis , Pyridones/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacologyABSTRACT
Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.
Subject(s)
Anti-HIV Agents/chemistry , Ethers/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Pyrazoles/chemistry , Pyridines/chemistry , Reverse Transcriptase Inhibitors/chemistry , Allosteric Regulation , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Dogs , Ethers/chemical synthesis , Ethers/pharmacokinetics , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , Humans , Mutation , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound also exhibited a clean safety profile in preclinical safety studies.
Subject(s)
Ethers/chemistry , Ethers/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/genetics , HIV-1/drug effects , HIV-1/genetics , Mutation , Animals , Cell Line , Dogs , Ethers/chemical synthesis , Ethers/pharmacokinetics , HIV-1/enzymology , Humans , Macaca mulatta , Nucleosides/chemistry , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.
