ABSTRACT
The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.
Subject(s)
Acetamides/pharmacology , Arachidonate 5-Lipoxygenase/metabolism , Drug Discovery , Lipoxygenase Inhibitors/pharmacology , Oxadiazoles/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Models, Molecular , Molecular Conformation , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Structure-Activity RelationshipABSTRACT
A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39.
ABSTRACT
Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.
Subject(s)
Drug Discovery , Glucocorticoids/chemical synthesis , Methanol/chemistry , Receptors, Glucocorticoid/agonists , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Arthritis/drug therapy , Binding Sites , Disease Models, Animal , Dose-Response Relationship, Drug , Glucocorticoids/chemistry , Glucocorticoids/pharmacology , Humans , Inhibitory Concentration 50 , Methanol/chemical synthesis , Methanol/pharmacology , Mice , Models, Molecular , Molecular Structure , Prednisolone/chemistry , Prednisolone/pharmacology , Protein Binding/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
A class of α-methyltryptamine sulfonamide glucocorticoid receptor (GR) modulators was optimized for agonist activity. The design of ligands was aided by molecular modeling, and key function-regulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell based assays. Compound 27 was profiled in vitro and in vivo in models of inflammation. Analogs could be rapidly prepared in a parallel approach from aziridine building blocks.
Subject(s)
Receptors, Glucocorticoid/agonists , Sulfonamides/chemistry , Sulfonamides/pharmacology , Tryptamines/chemistry , Tryptamines/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Arthritis/chemically induced , Arthritis/drug therapy , Binding Sites , Mice , Molecular Docking Simulation , Protein Binding/drug effects , Protein Structure, Tertiary , Receptors, Glucocorticoid/metabolism , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/therapeutic use , Tryptamines/metabolism , Tryptamines/therapeutic useABSTRACT
A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors.