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
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.