ABSTRACT
PURPOSE: Two allosteric modulators of the group I metabotropic glutamate receptors (mGluR1 and mGluR5) were evaluated as positron emission tomography (PET) radioligands for mGluR1. METHODS: LY2428703, a full mGluR1 antagonist (IC(50) 8.9 nM) and partial mGluR5 antagonist (IC(50) 118 nM), and LSN2606428, a full mGluR1 and mGluR5 antagonist (IC(50) 35.3 nM and 10.2 nM, respectively) were successfully labeled with (11)C and evaluated as radioligands for mGluR1. The pharmacology of LY2428703 was comprehensively assessed in vitro and in vivo, and its biodistribution was investigated by liquid chromatography-mass spectrometry/mass spectrometry, and by PET imaging in the rat. In contrast, LSN2606428 was only evaluated in vitro; further evaluation was stopped due to its unfavorable pharmacological properties and binding affinity. RESULTS: (11)C-LY2428703 showed promising characteristics, including: (1) high potency for binding to human mGluR1 (IC(50) 8.9 nM) with no significant affinity for other human mGlu receptors (mGluR2 through mGluR8); (2) binding to brain displaceable by administration of an mGluR1 antagonist; (3) only one major radiometabolite in both plasma and brain, with a negligible brain concentration (with 3.5 % of the total radioactivity in cerebellum) and no receptor affinity; (4) a large specific and displaceable signal in the mGluR1-rich cerebellum with no significant in vivo affinity for mGluR5, as shown by PET studies in rats; and (5) lack of substrate behavior for efflux transporters at the blood-brain barrier, as shown by PET studies conducted in wild-type and knockout mice. CONCLUSION: (11)C-LY2428703, a new PET radioligand for mGluR1 quantification, displayed promising characteristics both in vitro and in vivo in rodents.
Subject(s)
Brain/pathology , Carbon Isotopes/pharmacology , Positron-Emission Tomography/methods , Receptors, Metabotropic Glutamate/metabolism , Allosteric Site , Animals , Blood-Brain Barrier , Chromatography, Liquid/methods , Humans , In Vitro Techniques , Inhibitory Concentration 50 , Ligands , Male , Mice , Mice, Knockout , Models, Chemical , Rats , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methodsABSTRACT
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats.
Subject(s)
Antithrombin III/chemical synthesis , Antithrombin III/pharmacology , Glycine/analogs & derivatives , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacology , Antithrombin III/chemistry , Crystallography, X-Ray , Factor Xa/chemistry , Factor Xa/metabolism , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Humans , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity RelationshipABSTRACT
SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays.
Subject(s)
Antithrombin III/chemical synthesis , Factor Xa Inhibitors , Fluorescent Dyes/pharmacology , ortho-Aminobenzoates/pharmacology , Anticoagulants/chemistry , Antithrombin III/chemistry , Binding Sites , Chemistry, Pharmaceutical/methods , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Fluorescent Dyes/chemical synthesis , Humans , Kinetics , Models, Chemical , Molecular Conformation , Structure-Activity Relationship , ortho-Aminobenzoates/chemical synthesisABSTRACT
A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone (11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound (16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented.
Subject(s)
Alcohols/chemistry , Morpholines/pharmacology , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Crystallography, X-Ray , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Morpholines/chemistryABSTRACT
A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones have been discovered as potent and selective norepinephrine reuptake inhibitors. Efficient synthetic routes have been developed which allow for the multi-gram preparation of both final targets and advanced intermediates for SAR expansion.
Subject(s)
Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine/physiology , Quinolines/chemistry , Quinolines/pharmacology , Chromatography, High Pressure Liquid , Neurotransmitter Uptake Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Several non-amidino S1 derivatives of the 1,2-diaminobenzene-based scaffold (4) were synthesized and evaluated for their ability to bind to the active site and inhibit the human protease factor Xa. A subset of these compounds were also evaluated for their anticoagulant effects in human plasma as measured by prothrombin time (PT).
Subject(s)
Anticoagulants/chemical synthesis , Benzene Derivatives/chemical synthesis , Factor Xa Inhibitors , Anticoagulants/pharmacology , Benzene Derivatives/pharmacology , Binding Sites , Blood Coagulation/drug effects , Factor Xa/metabolism , Humans , Models, Molecular , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Binding , Prothrombin Time , Structure-Activity RelationshipABSTRACT
A novel isonitrile derivative was synthesized and used in an Ugi four component coupling reaction to explore aryl group substitution effects on inhibition of the coagulation cascade serine protease factor Xa.
