ABSTRACT
A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.
Subject(s)
Amines , Cyclohexanecarboxylic Acids , Osteoarthritis/drug therapy , Oxadiazoles/chemistry , Oxadiazoles/therapeutic use , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Brain/metabolism , Drug Interactions , Drug Therapy, Combination , Gabapentin , Octamer Transcription Factors , Organic Anion Transporters , Oxadiazoles/pharmacology , Pregabalin , RatsABSTRACT
A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.
Subject(s)
Amines/chemical synthesis , Amines/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Carboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/pharmacology , Tetrazoles/chemistry , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/pharmacology , Amines/chemistry , Animals , Anticonvulsants/chemical synthesis , Cyclohexanecarboxylic Acids/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Gabapentin , In Vitro Techniques , Mice , Mice, Inbred DBA , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/chemistryABSTRACT
Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.
