ABSTRACT
Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail.
Subject(s)
Hypoglycemic Agents/chemistry , Hypolipidemic Agents/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Administration, Oral , Animals , Binding Sites , Computer Simulation , Diabetes Mellitus, Experimental/drug therapy , Drug Evaluation, Preclinical , Dyslipidemias/drug therapy , Hypoglycemic Agents/administration & dosage , Hypolipidemic Agents/administration & dosage , Mice , Mice, Knockout , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, LDL/genetics , Receptors, LDL/metabolism , Structure-Activity RelationshipABSTRACT
We reported earlier the refinement of our initial five-point pharmacophore model for the Histamine 3 receptor (H(3)R), with a new acceptor feature important for binding and selectivity against the other histamine receptor subtypes 1, 2 and 4. This approach was validated with a new series of H(3)R inverse agonists: the naphthalene series. In this Letter, we describe our efforts to overcome the phospholipidosis flag identified with our initial lead compound (1a). During the optimization process, we monitored the potency of our molecules toward the H(3) receptor, their selectivity against H(1)R, H(2)R and H(4)R, as well as some key molecular properties that may influence phospholipidosis. Encouraged by the promising profile of the naphthalene series, we used our deeper understanding of the H(3)R pharmacophore model to lead us towards the quinoline series. This series is perceived to have intrinsic advantages with respect to its amphiphilic vector.
Subject(s)
Chemistry, Pharmaceutical/methods , Histamine Agonists/chemistry , Naphthalenes/chemistry , Phospholipids/chemistry , Quinolines/chemistry , Receptors, Histamine H3/chemistry , Animals , Drug Design , Humans , Hydrogen-Ion Concentration , Models, Chemical , Molecular Conformation , Molecular Structure , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H(3)R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]methanone 36 are detailed.
Subject(s)
Amides/chemistry , Histamine Agonists/therapeutic use , Indoles/chemistry , Obesity/drug therapy , Receptors, Histamine H3/drug effects , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Cell Membrane Permeability , Computational Biology , Drug Design , Histamine Agonists/pharmacokinetics , Histamine Agonists/pharmacology , Hydrophobic and Hydrophilic Interactions , Indoles/pharmacokinetics , Indoles/therapeutic use , Rats , Rats, Sprague-Dawley , Rats, Wistar , Structure-Activity RelationshipABSTRACT
A comparison between phosphine boranes and sulfides in their catalytic asymmetric deprotonation using organolithiums and sub-stoichiometric amounts of (-)-sparteine has revealed superior catalytic efficiency in the phosphine sulfide deprotonation.
Subject(s)
Boranes/chemical synthesis , Phosphines/chemical synthesis , Sulfides/chemical synthesis , Catalysis , Indicators and Reagents , Lithium/chemistry , Molecular Conformation , Protons , Solvents , Sparteine/chemistry , StereoisomerismABSTRACT
The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.
Subject(s)
Anti-Obesity Agents/administration & dosage , Anti-Obesity Agents/pharmacology , Benzodioxoles/administration & dosage , Benzodioxoles/pharmacology , Obesity/drug therapy , Receptor, Cannabinoid, CB1/agonists , Animals , Anti-Obesity Agents/chemistry , Benzodioxoles/chemical synthesis , Benzodioxoles/chemistry , Body Weight/drug effects , Crystallography, X-Ray , Cyclohexanols/antagonists & inhibitors , Cyclohexanols/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Humans , Hypothermia/chemically induced , Ligands , Male , Mice , Microsomes/drug effects , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/chemistry , Structure-Activity RelationshipABSTRACT
The catalytic asymmetric synthesis of planar chiral ferrocenes and P-stereogenic phosphines and bisphosphines (important classes of chiral ligands for metal-catalyzed asymmetric processes) is successfully demonstrated using n-BuLi or s-BuLi in combination with substoichiometric quantities (0.1-0.5 equiv) of (-)-sparteine or the (+)-sparteine surrogate.
ABSTRACT
Sets of isomeric thiazole derivatives 1 and 2 have been synthesised in a parallel iterative solution-phase synthesis approach guided by the SAR analysis derived from biological results and computer-aided design and analysis. This synergistic and streamlined working procedure led to highly active isomeric NPY5 receptor ligands. However, a 10-fold difference at least in their respective binding affinities was consistently found for all isomeric pairs 1 and 2. The analysis of conformational differences due to heteroatom interactions in 1 and 2 revealed a favourable C=O...S interaction in 1, whereas thiazoles 2 showed a repulsive C=O...N interaction.
