ABSTRACT
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Subject(s)
Analgesics/pharmacology , Analgesics/therapeutic use , Benzamides/pharmacology , Benzamides/therapeutic use , Benzopyrans/pharmacology , Benzopyrans/therapeutic use , Pain/drug therapy , Receptors, Opioid, delta/agonists , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use , Analgesics/administration & dosage , Analgesics/chemistry , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Benzopyrans/administration & dosage , Benzopyrans/chemistry , CHO Cells , Clinical Trials as Topic , Cricetinae , Cricetulus , Crystallography, X-Ray , Cytochrome P-450 CYP2D6 Inhibitors , Dogs , Dose-Response Relationship, Drug , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Hyperalgesia/drug therapy , Male , Rats , Rats, Sprague-Dawley , Spiro Compounds/administration & dosage , Spiro Compounds/chemistryABSTRACT
Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.
Subject(s)
Benzamides/therapeutic use , Neuralgia/drug therapy , Receptor, Cannabinoid, CB2/metabolism , Sulfonamides/therapeutic use , Animals , Benzamides/chemical synthesis , Benzamides/pharmacology , Binding Sites , Dose-Response Relationship, Drug , Ligands , Mice , Models, Animal , Models, Chemical , Pain Measurement/drug effects , Rats , Receptor, Cannabinoid, CB2/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
Synthesis, in vitro biological evaluation, and structure-activity relationships of a biaryl cannabinoid mimetic 2 are reported. Variations in the substitution pattern yielded a number of agonists with low nanomolar affinity. Replacing the phenol group by a methyl morpholino acetate group led to compound 28, a 500-fold selective CB(2) receptor agonist.
Subject(s)
Cannabinoids/chemistry , Cannabinoids/chemical synthesis , Chemistry, Pharmaceutical/methods , Carboxylic Acids/chemistry , Drug Design , Drug Evaluation, Preclinical , Humans , Hydrogen/chemistry , Hydrogen Bonding , Immunosuppressive Agents/chemistry , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Parasympatholytics , Phenol/chemistry , Protein BindingABSTRACT
10-Hydroxy-10,9-boroxarophenanthrenes were obtained as unexpected major products upon BBr(3)-mediated O-demethylation of 2-methoxybiaryls. The formation likely proceeds via intramolecular electrophilic aromatic cyclization of a reactive dibromoaryloxyborane intermediate. Essentially quantitative yields of 10-hydroxy-10,9-boroxarophenanthrenes were also obtained from 2-hydroxybiaryl and BCl(3)/AlCl(3) with use of a modified literature procedure. As synthetic intermediates, 10-hydroxy-10,9-boroxarophenanthrenes were efficiently converted to 3,4-benzocoumarins and triaryls through Pd-catalyzed CO insertion and Suzuki reaction.
