ABSTRACT
The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Interferons/agonists , Toll-Like Receptor 7/agonists , Aldehyde Oxidase/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Discovery , Drug Evaluation, Preclinical , Hepacivirus/physiology , Hepatitis C/virology , Humans , Injections, Intravenous , Interferon Inducers/chemical synthesis , Interferon Inducers/chemistry , Interferon Inducers/pharmacokinetics , Interferon Inducers/pharmacology , Microsomes, Liver/metabolism , Molecular Targeted Therapy , Molecular Weight , Purines/chemical synthesis , Purines/metabolism , Rats , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.
Subject(s)
Antiviral Agents/chemistry , Hepacivirus/drug effects , Purines/chemistry , RNA Virus Infections/drug therapy , Toll-Like Receptor 7/agonists , Administration, Oral , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , Drug Design , Mice , Models, Animal , Purines/pharmacokinetics , Purines/therapeutic use , Rats , Structure-Activity Relationship , Toll-Like Receptor 7/metabolismABSTRACT
The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.
