ABSTRACT
A range of 3,4-alkylated five-membered ring derivatives of gabapentin were synthesised. One compound (21) had an excellent level of potency against alpha(2)delta and was profiled in in vivo models of pain and anxiety.
Subject(s)
Amines/chemistry , Amino Acids/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cyclohexanecarboxylic Acids/chemistry , Cyclopentanes/chemical synthesis , gamma-Aminobutyric Acid/chemistry , Amines/chemical synthesis , Amines/pharmacokinetics , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/pharmacokinetics , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Disease Models, Animal , Gabapentin , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Rats , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
A range of 3-alkylated five-membered ring derivatives of Gabapentin were synthesized and several were found to have good levels of potency against the alpha2delta calcium subunit of a voltage-gated calcium channel. Two compounds were profiled in in vivo models of pain and anxiety.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclopentanes/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis , Amines/chemistry , Amines/pharmacology , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Calcium Channels/metabolism , Carrageenan/pharmacology , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacology , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Gabapentin , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Rats , Stereoisomerism , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
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
We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.
Subject(s)
Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Cricetulus , Rats , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/physiology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.
Subject(s)
Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , CHO Cells , Calcium/metabolism , Cricetinae , Cricetulus , Cyclooxygenase 2 Inhibitors/therapeutic use , Indicators and Reagents , Joints/pathology , Lactones/therapeutic use , Osteoarthritis/chemically induced , Osteoarthritis/drug therapy , Osteoarthritis/pathology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Receptor, Metabotropic Glutamate 5 , Structure-Activity Relationship , Sulfones/therapeutic useABSTRACT
Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.
Subject(s)
Drug Design , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Models, Molecular , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Receptor, Metabotropic Glutamate 5 , Structure-Activity RelationshipABSTRACT
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
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 (Lyrica) is a novel amino acid compound that binds with high affinity to the alpha2-delta (alpha2-delta) auxiliary protein of voltage-gated calcium channels. In vivo, it potently prevents seizures, pain-related behaviors and has anxiolytic-like activity in rodent models. The present studies were performed to determine the profile of pregabalin anticonvulsant activity in a variety of mouse and rat models. In the high-intensity electroshock test, pregabalin potently inhibited tonic extensor seizures in rats (ED50 = 1.8 mg/kg, PO), and low-intensity electroshock seizures in mice. It prevented tonic extensor seizures in the DBA/2 audiogenic mouse model (ED50 = 2.7 mg/kg, PO). Its time course of action against electroshock induced seizures in rats roughly followed the pharmacokinetics of radiolabeled drug in the brain compartment. At higher dosages (ED50 1= 31 mg/kg, PO), pregabalin prevented clonic seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4-5 behavioral seizures (lowest effective dose = 10 mg/kg, IP), and also reduced the duration of electrographic seizures. Pregabalin was not active to prevent spontaneous absence-like seizures in the Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) inbred Wistar rat strain. Pregabalin caused ataxia and decreased spontaneous locomotor activity at dosages 10-30-fold higher than those active to prevent seizures. These findings suggest that pregabalin has an anticonvulsant mechanism different from the prototype antiepileptic drugs and similar to that of gabapentin except with increased potency and bioavailability. In summary, our results show that pregabalin has several properties that favor treatment of partial seizures in humans.
Subject(s)
Anticonvulsants/pharmacokinetics , Behavior, Animal/drug effects , Epilepsy/drug therapy , Seizures/drug therapy , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Disease Models, Animal , Dose-Response Relationship, Drug , Epilepsy/metabolism , Female , Gait Ataxia/drug therapy , Gait Ataxia/metabolism , Kindling, Neurologic , Male , Mice , Mice, Inbred Strains , Motor Activity/drug effects , Pregabalin , Rats , Rats, Sprague-Dawley , Rats, Wistar , Seizures/chemically induced , Seizures/metabolism , gamma-Aminobutyric Acid/administration & dosage , gamma-Aminobutyric Acid/adverse effects , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
A series of heteroaromatic analogs of pregabalin has been identified that possess anticonvulsant activity in the DBA/2 mouse model. The methods of synthesis and preliminary pharmacology are discussed herein.
Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Seizures/prevention & control , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Anticonvulsants/chemical synthesis , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , In Vitro Techniques , Mice , Mice, Inbred DBA , Molecular Structure , Pregabalin , Stereoisomerism , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
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.
Subject(s)
Amino Acid Transport System L/metabolism , Analgesics/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Anticonvulsants/chemical synthesis , Calcium Channels/metabolism , gamma-Aminobutyric Acid/analogs & derivatives , gamma-Aminobutyric Acid/chemical synthesis , Amines/antagonists & inhibitors , Amines/metabolism , Analgesics/chemistry , Analgesics/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/antagonists & inhibitors , Cyclohexanecarboxylic Acids/metabolism , Gabapentin , In Vitro Techniques , Leucine/antagonists & inhibitors , Leucine/metabolism , Male , Mice , Mice, Inbred DBA , Pregabalin , Protein Binding , Protein Subunits/metabolism , Rats , Structure-Activity Relationship , Swine , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/pharmacologyABSTRACT
As part of a program aimed at generating compounds with affinity for the alpha(2)-delta subunit of voltage-gated calcium channels, several novel beta-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the alpha(2)-delta subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood-brain barrier.