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
Synthesis of a number of bicyclic five-membered ring derivatives of gabapentin led to the identification of two compounds, (-)-(11A) and (20A) which both had an excellent level of potency against alpha(2)delta and were profiled in an in vivo model of neuropathic pain.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis , Amines/chemistry , Amines/pharmacokinetics , Amino Acids/chemistry , Amino Acids/pharmacokinetics , Animals , Blood-Brain Barrier/metabolism , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , CHO Cells , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacokinetics , Gabapentin , Neuralgia/drug therapy , Pain Measurement , Rats , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
The synthesis and biological evaluation of a novel series of 2-aminoquinoline substituted piperidines and tropanes incorporating a homotropene moiety is herein described. The series exhibits potent antagonism of the CXCR3 receptor and superior physicochemical properties. Compound 24d was found to be orally bioavailable, and PK/PD studies suggested it as a suitable tool for studying the role of CXCR3 in models of disease.
Subject(s)
Quinolines/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Animals , Area Under Curve , Biological Availability , Mice , Mice, Inbred BALB C , Quinolines/chemistry , Quinolines/pharmacokineticsABSTRACT
The optimization of a series of 1-aryl-3-piperidinyl urea derivatives is described in which incorporation of tropenyl and homotropenyl moieties has led to significant improvements in activity and drug-like properties. Replacement of the central piperidine with an exo-tropanyl unit led to the identification of compound 15 which provides a combination of excellent potency against human and murine receptors, drug-like properties and pharmacokinetics, thus providing a valuable tool for the evaluation of CXCR3 antagonists in models of human disease.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Urea/analogs & derivatives , Animals , Cycloparaffins/chemistry , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Piperidines/pharmacokinetics , Urea/chemistry , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.
Subject(s)
Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Indoles/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Molecular Weight , Oxazoles/pharmacology , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Biological Transport, Active/drug effects , Caco-2 Cells , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , In Vitro Techniques , Indoles/chemistry , Leukocytes, Mononuclear/drug effects , Molecular Structure , Molecular Weight , Structure-Activity RelationshipABSTRACT
The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Quinazolines/chemistry , Quinazolines/pharmacology , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Conformation , Quinazolines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II and in vitro inhibitory value for PBMC proliferation are discussed.
