ABSTRACT
Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was designed by replacement of the pyrrole core with an indole scaffold and consequent cyclization of the C-2 position into a tricyclic beta-carboline template. The appropriate exploration of the position C-6 with a combination of H-bond acceptor groups coupled with bulky/lipophilic moieties led to the discovery of a new series of mGluR1 antagonists. These compounds exhibited a non-competitive behavior, excellent pharmacokinetic properties, and good in vivo activity in animal models of acute and chronic pain, after oral administration.
Subject(s)
Carbolines/chemical synthesis , Carbolines/pharmacokinetics , Excitatory Amino Acid Antagonists/chemical synthesis , Pain/drug therapy , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Administration, Oral , Analgesics/chemical synthesis , Analgesics/pharmacology , Animals , Carbolines/therapeutic use , Disease Models, Animal , Drug Design , Excitatory Amino Acid Antagonists/pharmacokinetics , Excitatory Amino Acid Antagonists/therapeutic use , Humans , Inhibitory Concentration 50 , Ligands , Mice , Structure-Activity RelationshipABSTRACT
Following the recent disclosure of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester as a potent and selective mGluR1 non-competitive antagonist, the use of a doubly (13)C-labeled analogue to identify, and consequently prevent, metabolically labile positions is reported.
Subject(s)
Esters , Pyrroles , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Carbon Radioisotopes/chemistry , Indicators and Reagents , Isotope Labeling , Magnetic Resonance Spectroscopy , Mass Spectrometry , Rats , Structure-Activity RelationshipABSTRACT
Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was developed through a cyclization of the C-2 position on the pyrrole N-1 nitrogen. The resulting pyrrolo[1,2-a]pyrazinones are potent and noncompetitive antagonists.
Subject(s)
Pyrazines/chemistry , Pyrazines/pharmacology , Pyrroles/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Inhibitory Concentration 50 , Molecular Structure , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity RelationshipABSTRACT
Following the recent disclosure of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester, a potent and selective mGluR1 non-competitive antagonist, we report here a detailed exploration of the C-2 position of this scaffold with the preparation of differently substituted amides. Great improvement of the pharmacokinetic properties has been achieved through this exercise.
Subject(s)
Esters/chemical synthesis , Esters/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Azides/chemical synthesis , Azides/pharmacokinetics , Chemical Phenomena , Chemistry, Physical , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Molecular Conformation , Rats , Solubility , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
Following the disclosure of 3-(1,2,2-trimethylpropyl) 4-[3,5-dimethyl-2-propyloxycarbonyl]pyrrolecarboxylate as a potent and selective mGluR1 non-competitive antagonist, the role and the importance of the pyrrole template were investigated. Different aromatic moieties were investigated as possible bio-isosteric replacement of the original scaffold and some of them were shown to be partially able to mimic the properties of the original pyrrole ring.
Subject(s)
Analgesics, Non-Narcotic/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Analgesics, Non-Narcotic/pharmacology , Animals , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Binding, Competitive/drug effects , CHO Cells , Cricetinae , Esters/chemical synthesis , Esters/pharmacology , Inhibitory Concentration 50 , Mice , Nociceptors/drug effects , Pain Measurement , Pyrroles/pharmacology , Rats , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/genetics , Spinal Cord/drug effects , Spinal Cord/metabolism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
Following the disclosure of 3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester [3,5-dimethyl PPP] as a potent and selective mGluR1 non-competitive antagonist, we report here further in vivo characterization of this important tool and disclose the investigation of the C-5 position, which led to very potent compounds.
