ABSTRACT
In Alzheimer's disease, the density and spread of aggregated tau protein track well with neurodegeneration and cognitive decline, making the imaging of aggregated tau a compelling biomarker. A structure-activity relationship exploration around an isoquinoline hit, followed by an exploration of tolerated fluorination positions, allowed us to identify 9 (JNJ-64326067), a potent and selective binder to aggregated tau with a favorable pharmacokinetic profile and no apparent off-target binding. This was confirmed in rat and monkey positron emission tomography studies using [18F]9.
Subject(s)
Drug Discovery , Fluorine Radioisotopes/metabolism , Isoquinolines/pharmacokinetics , Positron-Emission Tomography , Pyridines/pharmacokinetics , tau Proteins/metabolism , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Animals , Cells, Cultured , Female , Fluorine Radioisotopes/chemistry , Fluorine Radioisotopes/pharmacokinetics , Hepatocytes/metabolism , Humans , Isoquinolines/chemistry , Macaca mulatta , Male , Pyridines/chemistry , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Sulfonimidamides are an emerging bioisosteric replacement in medicinal chemistry projects, and therefore new chemistries are necessary to access this functionality. The general synthesis of CF3-sulfonimidamides from an activated bench-stable transfer reagent is described. A diverse reaction scope is demonstrated, with a wide range of nucleophilic amines being tolerated in this transformation. The CF3-sulfonimidamides obtained contain an additional diversity point, in the form a protected imine, that could be unmasked to allow late stage modifications.
ABSTRACT
A general synthesis of CF3-sulfonimidamides from sulfinamides under both batch and continuous flow conditions is described. The reaction proceeds via a sulfonimidoyl fluoride intermediate. A reaction scope showing good group variation on the substituents of both nitrogen atoms is also presented.
ABSTRACT
A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated ß-amyloid (Aß). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine 75, a potent and selective tau aggregate binder with potential as a tau PET tracer.
Subject(s)
Alzheimer Disease/diagnostic imaging , Amyloid beta-Peptides/analysis , Brain/diagnostic imaging , Naphthyridines/chemistry , Positron-Emission Tomography/methods , Protein Aggregation, Pathological/diagnostic imaging , tau Proteins/analysis , Amination , Animals , Haplorhini , Humans , Mice , Naphthyridines/pharmacokinetics , RatsABSTRACT
The synthesis, SAR and preclinical characterization of a series of 6-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists is described herein. The lead compounds are potent inhibitors in Ca(2+) flux and whole blood IL-1ß P2X7 release assays at both human and mouse isoforms. Compound 1e showed a robust reduction of IL-1ß release in a mouse ex vivo model with a 50mg/kg oral dose. Evaluation of compound 1e in the mouse SNI tactile allodynia, carrageenan-induced paw edema or CIA models resulted in no analgesic or anti-inflammatory effects.
Subject(s)
Purinergic P2X Receptor Antagonists/pharmacology , Quinolines/pharmacology , Animals , Drug Discovery , Humans , Interleukin-1beta/metabolism , Mice , Purinergic P2X Receptor Antagonists/chemistry , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
Novel 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives have been prepared and their synthesis described herein. In vitro affinities for delta-, micro-, and kappa-opioid receptors are reported. Evaluation of some representative compounds from this series in the mouse neonatal ultrasonic vocalization test and the mouse tail suspension test revealed anxiolytic- and antidepressant-like effects, respectively, upon subcutaneous administration.
Subject(s)
Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacology , Piperidines/pharmacology , Receptors, Opioid, delta/agonists , Anti-Anxiety Agents/chemistry , Antidepressive Agents/chemistry , Piperidines/chemistryABSTRACT
A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for delta-, mu-, and kappa-opioid receptors, as well as the functional activity in the [(35)S]GTPgammaS assay are reported. The most potent and selective delta-opioid agonist 18a exhibited a K(i) of 18 nM, and was >258-fold and 28-fold selective over mu- and kappa-receptors, respectively; the compound is a full agonist with an EC(50) value of 14 nM.
