ABSTRACT
A novel series of N-type calcium channel inhibitors have been discovered. Optimization of potency and HT-ADME properties provides 4-aminocyclopentapyrrolidines with analgesic efficacy after oral dosing.
Subject(s)
Analgesics/chemistry , Analgesics/therapeutic use , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/therapeutic use , Calcium Channels, N-Type/metabolism , Neuralgia/drug therapy , Administration, Oral , Analgesics/chemical synthesis , Analgesics/metabolism , Animals , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/metabolism , Humans , Microsomes/metabolism , Rats , Structure-Activity RelationshipABSTRACT
A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels. N-type Ca(2+) channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca(2+) channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.
Subject(s)
Acetamides/chemical synthesis , Analgesics/chemical synthesis , Calcium Channel Blockers/chemical synthesis , Calcium Channels, N-Type/chemistry , Pyrrolidines/chemistry , Pyrrolidines/chemical synthesis , Acetamides/pharmacology , Acetamides/therapeutic use , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Behavior, Animal/drug effects , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Calcium Channels, N-Type/metabolism , Disease Models, Animal , Male , Pain/drug therapy , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Potent small molecule antagonists for the PAC(1)-R have been discovered. Previously known antagonists for the PAC(1)-R were slightly truncated peptide ligands. The hydrazides reported here are the first small molecule antagonists ever reported for this class B GPCR.
Subject(s)
Hydrazines/chemistry , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/antagonists & inhibitors , Calcium/metabolism , Cells, Cultured , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Radioligand Assay , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Structure-Activity RelationshipABSTRACT
A series of novel 6-O-arylpropargyl-9-oxime-ketolides was synthesized and evaluated against various pathogens. These new compounds show promising in vitro antibacterial potency and in vivo efficacy against macrolide resistant strains.
Subject(s)
Ketolides/chemical synthesis , Ketolides/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Disease Models, Animal , Drug Resistance, Bacterial , Haemophilus influenzae/drug effects , Ketolides/therapeutic use , Macrolides , Rats , Respiratory Tract Infections/drug therapy , Staphylococcus/drug effects , Structure-Activity RelationshipABSTRACT
The parallel synthesis and antibacterial activity of 5-hydroxy[1,2,5] oxadiazolo[3,4-b]pyrazines is reported. The compounds were synthesized by condensing diaminofurazan with alpha-keto acids to give a variety of aryl-substituted analogues. Halogenated phenyl groups at C-6 give rise to the greatest Haemophilus influenzae antibacterial activity.
