ABSTRACT
Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.
Subject(s)
Isoxazoles/chemistry , Proline/chemistry , Pyrrolidonecarboxylic Acid/analogs & derivatives , Receptor, Cannabinoid, CB2/agonists , Animals , Diabetic Neuropathies/chemically induced , Diabetic Neuropathies/drug therapy , Half-Life , Humans , Isoxazoles/pharmacokinetics , Isoxazoles/therapeutic use , Ligands , Male , Microsomes, Liver/metabolism , Proline/pharmacokinetics , Proline/therapeutic use , Protein Binding , Pyrrolidonecarboxylic Acid/chemistry , Pyrrolidonecarboxylic Acid/pharmacokinetics , Pyrrolidonecarboxylic Acid/therapeutic use , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.
Subject(s)
Pipecolic Acids/chemistry , Piperidines/chemistry , Receptor, Cannabinoid, CB2/agonists , Thiazines/chemistry , Animals , Diabetic Neuropathies/chemically induced , Diabetic Neuropathies/drug therapy , Half-Life , Humans , Ligands , Male , Microsomes, Liver/metabolism , Pain/drug therapy , Pipecolic Acids/pharmacokinetics , Pipecolic Acids/therapeutic use , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Protein Binding , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Solubility , Structure-Activity Relationship , Thiazines/pharmacokinetics , Thiazines/therapeutic useABSTRACT
A molecular understanding of the proteins involved in fructose metabolism is essential for controlling the current spread of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism starts with the phosphorylation of D-fructose to fructose 1-phosphate by ketohexokinase (KHK). KHK exists in two alternatively spliced isoforms: the hepatic and intestinal isoform KHK-C and the peripheral isoform KHK-A. Here, the structure of apo murine KHK (mKHK), which differs from structures of human KHK in overall conformation, is reported. An isoform-selective ligand, which offers a 50-fold higher potency on mKHK and human KHK-A compared with KHK-C, is further characterized. In mKHK, large-scale conformational changes are observed upon ligand binding. The structures suggest a combined strategy for the design of species- and isoform-selective KHK inhibitors.
ABSTRACT
Autotaxin (ATX) is a promising drug target for the treatment of several diseases, such as cancer and fibrosis. ATX hydrolyzes lysophosphatidyl choline (LPC) into bioactive lysophosphatidic acid (LPA). The potency of ATX inhibitors can be readily determined by using fluorescence-based LPC derivatives. While such assays are ultra-high throughput, they are prone to false positives compared to assays based on natural LPC. Here we report the development of ultrafast mass spectrometry-based ATX assays enabling the measurement of data points within 13 s, which is 10 times faster than classic liquid chromatography-mass spectrometry. To this end, we set up a novel in vitro and whole-blood assay. We demonstrate that the potencies determined with these assays are in good agreement with the in vivo efficacy and that the whole-blood assay has the best predictive power. This high-throughput label-free approach paired with the translatable data quality is highly attractive for appropriate guidance of medicinal chemists for constructing strong structure-activity relationships.
Subject(s)
Enzyme Inhibitors/blood , High-Throughput Screening Assays , Lysophosphatidylcholines/blood , Lysophospholipids/blood , Mass Spectrometry/methods , Phosphoric Diester Hydrolases/blood , Animals , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haplorhini , Humans , Hydrolysis , Lysophosphatidylcholines/chemistry , Lysophospholipids/antagonists & inhibitors , Lysophospholipids/chemistry , Rats , Rats, Wistar , Recombinant Proteins/bloodABSTRACT
In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies.