ABSTRACT
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Subject(s)
Biphenyl Compounds/chemistry , Neuralgia/drug therapy , Pyrazoles/chemistry , Sodium Channel Blockers/chemistry , Sodium Channels/chemistry , Animals , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/therapeutic use , Dogs , Drug Evaluation, Preclinical , Humans , Mice , Microsomes, Liver/metabolism , Motor Activity/drug effects , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolismABSTRACT
The preparation and structure-activity-relationships of novel pyrrolidine-carboxamides and oxadiazoles are described. Compounds in this series were found to be potent hNK(1) antagonists in vitro and efficacious in vivo with minimal interactions with P(450) liver enzymes. Oxadiazole analog 22 was determined to have excellent hNK(1) binding affinity, functional activity, and a good PD response in vivo.
Subject(s)
Alkaloids/pharmacology , Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Menispermaceae/chemistry , Oxadiazoles/pharmacology , Pyrrolidines/pharmacology , Alkaloids/chemistry , Antiviral Agents/chemistry , Cell Line , Chromatography, Ion Exchange , Hepatitis B Surface Antigens/metabolism , Hepatitis B e Antigens/metabolism , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Oxadiazoles/chemistry , Pyrrolidines/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml.
Subject(s)
Neurokinin-1 Receptor Antagonists , Pyrrolidines/pharmacology , Administration, Oral , Animals , Biological Availability , Brain/metabolism , Humans , Macaca mulatta , Pyrrolidines/pharmacokinetics , Species SpecificityABSTRACT
A series of 2-aminoquinoline compounds was prepared and evaluated in MCH1R binding and functional antagonist assays. Small dialkyl, methylalkyl, methylcycloalkyl, and cyclic amines were tolerated at the quinoline 2-position. The in vivo efficacy of compound 12 was explored and compared to that of a related inactive analog to determine their effects on food intake and body weight in rodents.
