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
A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described.
Subject(s)
Amides/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/chemistry , Sulfonamides/chemistry , Amides/chemical synthesis , Amides/metabolism , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Peptide Fragments/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Protein Binding , Structure-Activity RelationshipABSTRACT
During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-ß precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aß40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aß40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
ABSTRACT
The amyloid-beta (Abeta) peptide, which likely plays a key role in Alzheimer disease, is derived from the amyloid-beta precursor protein (APP) through consecutive proteolytic cleavages by beta-site APP-cleaving enzyme and gamma-secretase. Unexpectedly gamma-secretase inhibitors can increase the secretion of Abeta peptides under some circumstances. This "Abeta rise" phenomenon, the same inhibitor causing an increase in Abeta at low concentrations but inhibition at higher concentrations, has been widely observed. Here we show that the Abeta rise depends on the beta-secretase-derived C-terminal fragment of APP (betaCTF) or C99 levels with low levels causing rises. In contrast, the N-terminally truncated form of Abeta, known as "p3," formed by alpha-secretase cleavage, did not exhibit a rise. In addition to the Abeta rise, low betaCTF or C99 expression decreased gamma-secretase inhibitor potency. This "potency shift" may be explained by the relatively high enzyme to substrate ratio under conditions of low substrate because increased concentrations of inhibitor would be necessary to affect substrate turnover. Consistent with this hypothesis, gamma-secretase inhibitor radioligand occupancy studies showed that a high level of occupancy was correlated with inhibition of Abeta under conditions of low substrate expression. The Abeta rise was also observed in rat brain after dosing with the gamma-secretase inhibitor BMS-299897. The Abeta rise and potency shift are therefore relevant factors in the development of gamma-secretase inhibitors and can be evaluated using appropriate choices of animal and cell culture models. Hypothetical mechanisms for the Abeta rise, including the "incomplete processing" and endocytic models, are discussed.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Gene Expression Regulation, Enzymologic , Animals , Brain/metabolism , Butyrates/pharmacology , Cell Line , Enzyme Inhibitors/pharmacology , Female , Humans , Hydrocarbons, Halogenated/pharmacology , Mice , Protein Binding , Protein Structure, Tertiary , Rats , Substrate SpecificityABSTRACT
The synthesis and gamma-secretase inhibition data for a series of carbamate-appended N-alkylsulfonamides are described. Carbamate 54 was found to significantly reduce brain Abeta in transgenic mice. 54 was also found to possess markedly improved brain levels in transgenic mice compared to previously disclosed 1 and 2.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Carbamates/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Brain/drug effects , Brain/metabolism , Mice , Mice, Transgenic , Structure-Activity RelationshipABSTRACT
The synthesis and gamma-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Abeta in transgenic mice was demonstrated by two of these compounds (23 and 44).
Subject(s)
Amines/chemistry , Amines/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Alkylation , Amines/chemical synthesis , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Azoles/chemical synthesis , Azoles/chemistry , Azoles/pharmacology , Brain/drug effects , Brain/enzymology , Brain/metabolism , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Mice , Mice, Transgenic , Peptide Fragments/metabolism , Protease Inhibitors/chemical synthesis , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.
