ABSTRACT
The syntheses and SAR investigations of novel CB(1) receptor antagonists based on a 1,2-diaryl piperidine core have been described. Optimization of this core afforded a compound with robust in vivo potency by reducing food intake in a mouse DIO model.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Diet/adverse effects , Eating/drug effects , Eating/physiology , Mice , Mice, Obese , Obesity/etiology , Obesity/metabolism , Piperidines/administration & dosage , Protein Binding/physiology , Receptor, Cannabinoid, CB1/metabolism , Structure-Activity RelationshipABSTRACT
CB1 receptor antagonists have proven to be clinically effective in treating obesity and related disorders. We report here the identification of a novel class of azetidinone CB1 antagonists by using virtual screening methods. For this purpose, we developed a pharmacophore model based on known representative CB1 antagonists and employed it to screen a database of about a half million Schering-Plough compounds. We applied a stepwise filtering protocol based on molecular weight, compound availability, and a modified rule-of-five to reduce the number of hits. We then combined Bayesian modeling and clustering techniques to select a final set of 420 compounds for in vitro testing. Five compounds were found to have >50% inhibition at 100 nM in a CB1 competitive binding assay and were further characterized by using both CB1 and CB2 assays. The most potent compound has a CB1 K i of 53 nM and >5-fold selectivity against the CB2 receptor.
Subject(s)
Drug Evaluation, Preclinical , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Bayes Theorem , Models, Molecular , Protein Binding , Receptor, Cannabinoid, CB1/metabolismABSTRACT
The structure-activity relationship (SAR) of the vinyl pyridine region of himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Furans/chemistry , Furans/pharmacology , Naphthalenes/chemistry , Naphthalenes/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptor, PAR-1/antagonists & inhibitors , Animals , Anticoagulants/chemistry , Anticoagulants/pharmacology , Molecular Structure , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
The structure-activity relationship (SAR) of the lactone ring of himbacine derived thrombin receptor (PAR-1) antagonists (e.g., 2-5) is described. The effect of the lactone carbonyl group on binding to PAR-1 is dependent on the substitution pattern of the pyridine ring. A stereoselective intramolecular Michael addition reaction to the vinyl pyridine group was observed for these pyridine analogs of himbacine in basic conditions at elevated temperature.
