ABSTRACT
We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.
ABSTRACT
We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.
ABSTRACT
For over three decades, the design of linear peptide ligands often has incorporated cyclic constraints to improve potency, receptor selectivity, proteolytic stability and biodistribution. Its importance has been so well established that modern day schemes for ligand-based drug design often start with cyclization of linear peptides to rigidify peptide structure, to limit its conformational possibilities, and to find key pharmacophore elements in three-dimensional space. In the past several years, cyclic constraints have been used to develop ligands with improved efficacy, binding affinity, biostability and receptor selectivity for alpha-melanocyte-stimulating hormone (alpha-MSH). Furthermore, potent cyclic alpha-MSH analogues, such as MT-II and SHU-9119, have made structure-activity relationship studies and molecular modeling more useful for creating new three-dimensional, topographical pharmacophore templates.
