ABSTRACT
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
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , HIV-1/enzymology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Administration, Oral , Animals , Bromine Compounds/chemical synthesis , Bromine Compounds/chemistry , Crystallography, X-Ray , Drug Evaluation, Preclinical , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/genetics , Models, Molecular , Molecular Structure , Mutation/genetics , Nucleosides/chemistry , Nucleosides/pharmacology , Pyrazoles/chemistry , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Using a combination of traditional Medicinal Chemistry/SAR analysis, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad antiviral activity against a number of key clinical mutations.
Subject(s)
Anti-HIV Agents/pharmacology , Drug Design , Ethers/chemistry , HIV-1/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Virus Replication/drug effects , Anti-HIV Agents/chemical synthesis , Binding Sites , Crystallography, X-Ray , Drug Resistance, Viral , HIV-1/enzymology , HIV-1/genetics , Models, Chemical , Mutation , Nucleosides/chemistry , Reverse Transcriptase Inhibitors/chemical synthesis , Structure-Activity Relationship , Virus Replication/physiologyABSTRACT
Pyrimidino-thiazolyl carbonitriles were prepared that are potent VEGFR-2 (KDR) kinase inhibitors. The modification of lead structures resulted in 3m which exhibited the best overall profile in KDR inhibitory activity, iv/po pharmacokinetics, and reduced hERG affinity.
Subject(s)
Nitriles/chemical synthesis , Nitriles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Dogs , Macaca mulatta , Molecular Structure , Nitriles/chemistry , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Rats , Sensitivity and Specificity , Structure-Activity Relationship , Thiazoles/chemistry , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
We have prepared a series of potent, dual inhibitors of the prenyl transferases farnesyl protein transferase (FPTase) and geranyl-geranyl protein transferase I (GGPTase). The compounds were shown to possess potent activity against both enzymes in cell culture. Mechanistic analysis has shown that the compounds are CAAX competitive for FPTase inhibition but geranyl-geranyl pyrophosphate (GGPP) competitive for GGPTase inhibiton.
