ABSTRACT
NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylamines/chemistry , Ethylamines/pharmacology , Peptides/chemistry , Peptides/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Brain/metabolism , Crystallography, X-Ray , Cyclization , Drug Design , Ethylamines/pharmacokinetics , Humans , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Morpholines/chemistry , Morpholines/pharmacokinetics , Morpholines/pharmacology , Peptides/pharmacokinetics , Protease Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Receptors, Metabotropic Glutamate/agonists , Triazoles/chemistry , Allosteric Regulation , Animals , Binding, Competitive , Bridged Bicyclo Compounds/pharmacokinetics , Bridged Bicyclo Compounds/pharmacology , Calcium/metabolism , Cyclic AMP/metabolism , Dogs , Drug Partial Agonism , Humans , Male , Mice , Models, Molecular , Motor Activity/drug effects , Mutagenesis, Site-Directed , Protein Structure, Tertiary , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, Metabotropic Glutamate/genetics , Receptors, Metabotropic Glutamate/metabolism , Stereoisomerism , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4ß-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.
Subject(s)
Bridged Bicyclo Compounds/pharmacology , Receptors, Metabotropic Glutamate/agonists , Spiro Compounds/pharmacology , Animals , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/metabolism , Crystallography, X-Ray , Humans , Male , Models, Molecular , Protein Structure, Tertiary , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/genetics , Spiro Compounds/chemistry , Spiro Compounds/metabolismABSTRACT
SAR around a known molecule with dual 5-HT(1D) antagonist and 5-HT(transporter) inhibitory activity has led to the discovery of molecules with improved dual activity and reduced cross-reactivity toward other aminergic receptors (5-HT(1B), alpha(1), and D(2)).
Subject(s)
Antidepressive Agents/pharmacology , Naphthalenes/chemistry , Piperazines/pharmacology , Receptor, Serotonin, 5-HT1D/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Antagonists/pharmacology , Animals , Antidepressive Agents/chemical synthesis , Dose-Response Relationship, Drug , Guinea Pigs , Kinetics , Models, Chemical , Piperazines/chemical synthesis , Receptor, Serotonin, 5-HT1D/metabolism , Serotonin Antagonists/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis of a series of C3'-cis-substituted carboxycyclopropyl glycines bearing a wide variety of functional groups is described, and the structure-activity relationship for this series as agonists of group II metabotropic glutamate receptors is reported.
Subject(s)
Glycine/chemistry , Glycine/pharmacology , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/metabolism , Crystallography, X-Ray , Cyclization , Glycine/chemical synthesis , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
The asymmetric synthesis and biological activity of (2S,1'S,2'R,3'R)-2-(2'-carboxy-3'-hydroxymethylcyclopropyl) glycine ((+)-3) is described. This novel C-3' substituted carboxy cyclopropyl glycine is a highly potent group 2 and group 3 mGluR agonist that has proven to be orally active in both fear potentiated startle (animal model for anxiety) and PCP-induced motor activation (animal model for psychosis) assays in rats.