ABSTRACT
DNA-encoded libraries (DELs) have generated recent interest due to their ability to provide new small molecule ligands for pharmaceutically important proteins. The chemical diversity of DELs determines their ability to provide potent, novel, and drug-like chemical matter, and DEL chemical diversity is limited by the scope of DNA-compatible chemical reactions. Herein, the one-pot three-component Van Leusen chemistry is applied to DEL synthesis, providing the first reported DNA-compatible method to generate novel highly functionalized imidazoles.
Subject(s)
DNA/chemistry , Imidazoles/chemical synthesis , Cyclization , Imidazoles/chemistry , Molecular Structure , Small Molecule LibrariesABSTRACT
The importance of Discoidin Domain Receptor 1 (DDR1) in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein, while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivo model have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitro safety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45 modulates DDR1 phosphorylation in vitro as well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45 preserves renal function and reduces tissue damage in Col4a3-/- mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3-/- mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population.
Subject(s)
DNA/genetics , Discoidin Domain Receptor 1/antagonists & inhibitors , Kidney/physiopathology , Nephritis, Hereditary/genetics , Animals , Autoantigens/genetics , Autoantigens/metabolism , Collagen Type IV/genetics , Collagen Type IV/metabolism , Discoidin Domain Receptor 1/metabolism , Disease Models, Animal , Epithelial Cells/metabolism , Kidney Function Tests , Mice , Mice, Knockout , Nephritis, Hereditary/physiopathology , Phosphorylation , Src Homology 2 Domain-Containing, Transforming Protein 1/metabolismABSTRACT
To optimize future DNA-encoded library design, we have attempted to quantify the library size at which the signal becomes undetectable. To accomplish this we (i) have calculated that percent yields of individual library members following a screen range from 0.002 to 1%, (ii) extrapolated that â¼1 million copies per library member are required at the outset of a screen, and (iii) from this extrapolation predict that false negative rates will begin to outweigh the benefit of increased diversity at library sizes >108. The above analysis is based upon a large internal data set comprising multiple screens, targets, and libraries; we also augmented our internal data with all currently available literature data. In theory, high false negative rates may be overcome by employing larger amounts of library; however, we argue that using more than currently reported amounts of library (â«10 nmoles) is impractical. The above conclusions may be generally applicable to other DNA encoded library platforms, particularly those platforms that do not allow for library amplification.
Subject(s)
DNA/chemistry , Combinatorial Chemistry Techniques , Drug Discovery , Molecular Structure , Small Molecule LibrariesABSTRACT
The introduction of N-substituted pyrazoles in a new series of CCR5 antagonists was shown to substantially increase antiviral activity.
Subject(s)
Anti-HIV Agents/chemistry , CCR5 Receptor Antagonists , Pyrazoles/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Humans , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, CCR5/metabolism , Structure-Activity RelationshipABSTRACT
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Subject(s)
Anti-HIV Agents/chemistry , Benzamides/chemistry , CCR5 Receptor Antagonists , HIV Fusion Inhibitors/chemistry , Pyrroles/chemistry , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Benzamides/chemical synthesis , Benzamides/pharmacology , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Rats , Receptors, CCR5/metabolism , Structure-Activity RelationshipABSTRACT
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc.
Subject(s)
Anti-HIV Agents/chemistry , Azabicyclo Compounds/chemistry , CCR5 Receptor Antagonists , Cyclohexanes/chemistry , HIV Fusion Inhibitors/chemistry , Triazoles/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Cell Line, Tumor , Cyclohexanes/chemical synthesis , Cyclohexanes/pharmacology , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/pharmacology , Humans , Maraviroc , Models, Chemical , Receptors, CCR5/metabolism , Triazoles/chemical synthesis , Triazoles/pharmacologyABSTRACT
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the conformationally restricted 4-aminopiperidine ring found in several series of CCR5 antagonists.
Subject(s)
CCR5 Receptor Antagonists , Drug Evaluation, Preclinical , Piperidines/chemistry , Models, MolecularABSTRACT
Replacement of a secondary amide with an N-acyl or N-sulfonyl gem-disubstituted azacyle in a series of CCR5 antagonists led to the identification of compounds with excellent in vitro HIV antiviral activity and increased intrinsic membrane permeability.