ABSTRACT
Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/chemistry , 5-Lipoxygenase-Activating Proteins/metabolism , Oxadiazoles/chemistry , 5-Lipoxygenase-Activating Protein Inhibitors/metabolism , 5-Lipoxygenase-Activating Proteins/chemistry , Animals , Drug Evaluation, Preclinical , ERG1 Potassium Channel/antagonists & inhibitors , ERG1 Potassium Channel/metabolism , Half-Life , Humans , Inhibitory Concentration 50 , Male , Microsomes, Liver/metabolism , Oxadiazoles/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Solubility , Structure-Activity RelationshipABSTRACT
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
We report on the nuclear receptor binding affinities, cellular activities of transrepression and transactivation, and anti-inflammatory properties of a quinol-4-one and other A-ring mimetic containing nonsteroidal class of glucocorticoid agonists.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Glucocorticoids/agonists , Molecular Mimicry , Quinolones/pharmacology , Receptors, Cytoplasmic and Nuclear/metabolism , Trans-Activators/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Aromatase/metabolism , Dexamethasone/pharmacology , Female , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , HeLa Cells , Humans , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Quinolones/chemical synthesis , Quinolones/chemistry , Trans-Activators/chemical synthesis , Trans-Activators/chemistry , Transcriptional ActivationABSTRACT
Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule.
