ABSTRACT
Pulmonary arterial hypertension (PAH) is a devastating rare disease, which despite currently available treatments, still represents a high unmet medical need. Specific E3 ubiquitin protein ligase 1 (SMURF1) is a HECT E3 ligase that ubiquitinates key signaling molecules from the TGFß/BMP pathways, which are of great relevance in the pathophysiology of PAH. Herein, the design and synthesis of novel potent small-molecule SMURF1 ligase inhibitors are described. Lead molecule 38 has demonstrated good oral pharmacokinetics in rats and significant efficacy in a rodent model of pulmonary hypertension.
Subject(s)
Pulmonary Arterial Hypertension , Ubiquitin-Protein Ligases , Rats , Animals , Ubiquitin-Protein Ligases/metabolism , Ubiquitin/metabolism , Ubiquitination , Lung/metabolismABSTRACT
To understand the relationship between structural properties of the ß2-adrenoceptor ligands and their interactions with membranes, we have investigated the location and distribution of five ß2 agonists with distinct clinical durations and onsets of action (indacaterol, two indacaterol analogues, salmeterol and formoterol) in monounsaturated model membranes using magic angle spinning NMR to measure these interactions through both 1H nuclear Overhauser enhancement (NOE) and paramagnetic relaxation enhancement (PRE) techniques. The hydrophilic aromatic groups of all five ß2 agonists show maximum distribution in the lipid/water interface, but distinct location and dynamic behavior were observed for the lipophilic aromatic rings. Our study elucidates at atomic level that the hydrophobicity and substitution geometry of lipophilic groups play important roles in compound-lipid interactions.
Subject(s)
Adrenergic beta-2 Receptor Agonists/chemistry , Liposomes/chemistry , Formoterol Fumarate/chemistry , Hydrophobic and Hydrophilic Interactions , Indans/chemistry , Ligands , Magnetic Resonance Spectroscopy , Phosphatidylcholines/chemistry , Quinolones/chemistry , Salmeterol Xinafoate/chemistryABSTRACT
A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.
Subject(s)
Airway Remodeling/drug effects , Hypertension, Pulmonary/drug therapy , Niacinamide/analogs & derivatives , Pyrazoles/chemistry , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Vascular Remodeling/drug effects , Administration, Inhalation , Animals , Cell Line , Cell Proliferation , Hypertension, Pulmonary/pathology , Lung/blood supply , Membranes, Artificial , Molecular Docking Simulation , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/pathology , Niacinamide/chemical synthesis , Niacinamide/chemistry , Niacinamide/pharmacology , Permeability , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Proto-Oncogene Proteins c-kit/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Rats , Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor alpha/chemistry , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor beta/chemistry , Receptors, Platelet-Derived Growth Factor/chemistry , Structure-Activity RelationshipABSTRACT
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice).
Subject(s)
Cyclohexanes/administration & dosage , Cyclohexanes/pharmacology , Endopeptidases/drug effects , Enzyme Inhibitors/pharmacology , Sulfones/administration & dosage , Sulfones/pharmacology , Administration, Oral , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides/drug effects , Animals , Aspartic Acid Endopeptidases , Brain/drug effects , Brain/metabolism , Cyclohexanes/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Mice , Molecular Structure , Peptide Fragments/drug effects , Structure-Activity Relationship , Sulfones/chemistry , Time FactorsABSTRACT
A series of novel 4,4-disubstituted cyclohexylamine based NK(1) antagonists is described. The effect of changes to the C(1)-C(4) relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.