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
The discovery and SAR of a series of beta-aryl substituted pyrrolidine 2H-isoquinolin-1-one inhibitors of Rho-kinase (ROCK) derived from 2 is herein described. SAR studies have shown that aryl groups in the beta-position are optimal for potency. Our efforts focused on improving the ROCK potency of this isoquinolone class of inhibitors which led to the identification of pyrrolidine 32 which demonstrated a 10-fold improvement in aortic ring (AR) potency over 2.
Subject(s)
Isoquinolines/chemistry , Protein Kinase Inhibitors/chemistry , Pyrrolidines/chemical synthesis , rho-Associated Kinases/antagonists & inhibitors , Animals , Aorta/drug effects , Crystallography, X-Ray , Drug Design , Hypertension/drug therapy , Inhibitory Concentration 50 , Isoquinolines/pharmacology , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.
