ABSTRACT
New cholecystokinin-1 receptor (CCK1R) agonist 'triggers' were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R's located within the intestinal wall.
Subject(s)
Amides/chemical synthesis , Drug Discovery , Piperidines/chemical synthesis , Receptor, Cholecystokinin A/agonists , Amides/chemistry , Amides/pharmacology , Animals , Cells, Cultured , Disease Models, Animal , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Obese , Piperidines/chemistry , Piperidines/pharmacology , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Weight Loss/drug effectsABSTRACT
A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse.
Subject(s)
Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Stearoyl-CoA Desaturase/antagonists & inhibitors , Administration, Oral , Enzyme Inhibitors/administration & dosage , Imidazoles/administration & dosage , Mass SpectrometryABSTRACT
We describe the design, synthesis, and structure-activity relationships of triazolobenzodiazepinone CCK1 receptor agonists. Analogs in this series demonstrate potent agonist activity as measured by in vitro and in vivo assays for CCK1 agonism. Our efforts resulted in the identification of compound 4a which significantly reduced food intake with minimal systemic exposure in rodents.
