ABSTRACT
Iterative structure-activity analyses in a class of highly functionalized furo[2,3-b]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (14), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 (14) is described.
ABSTRACT
The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase via binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 (43) as a preclinical candidate.
ABSTRACT
Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.
Subject(s)
Antiviral Agents/pharmacology , Benzazepines/pharmacology , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Regulation , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Benzazepines/chemistry , Benzazepines/pharmacokinetics , Dogs , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
The synthesis of novel ligands for the NPY(2) receptor using solid phase split pool methodology is described. One of the analogues, diamine 16, was found to be a potent NPY(2) binder.
Subject(s)
Diamines/metabolism , Receptors, Neuropeptide Y/metabolism , Acylation , Cell Line, Tumor , Diamines/chemical synthesis , Humans , Inhibitory Concentration 50 , Ligands , Neuroblastoma/metabolism , Radioligand Assay , Structure-Activity RelationshipABSTRACT
(E)-3-(Benzenesulfonyl)-2-(methylsulfanyl)pyrido[1,2-a]pyrimidin-4-ylidenamine (7) was found to be a potent and selective 5-HT(6) antagonist. A one-step synthesis of this compound is described.
Subject(s)
Acrylonitrile/chemistry , Pyrimidines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Sulfones/chemistry , Sulfones/chemical synthesis , Acrylonitrile/analogs & derivatives , Calcium/metabolism , Cell Line , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Humans , Models, Molecular , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfones/pharmacologyABSTRACT
The anti-influenza activity of a series of thiobenzamide fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine is profiled. Axial disposition of the thioamide moiety is essential for potent influenza inhibitory activity.
