ABSTRACT
Several beta-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the alpha(2)-delta protein examined. Two select compounds with potent affinity for alpha(2)-delta, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Carboxylic Acids/chemistry , Epilepsy, Reflex/prevention & control , gamma-Aminobutyric Acid/analogs & derivatives , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Animals , Anticonvulsants/chemistry , Binding Sites , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacology , Disease Models, Animal , Drug Evaluation, Preclinical , Gabapentin , Mice , Mice, Inbred DBA , Molecular Structure , Pregabalin , Protein Subunits/drug effects , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.
