ABSTRACT
The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1ß, and S1' pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.
Subject(s)
Factor XIa/antagonists & inhibitors , Factor XIa/genetics , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/chemistry , Administration, Oral , Amino Acid Sequence , Animals , Biological Availability , Dogs , Drug Evaluation, Preclinical/methods , Humans , Male , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Antibacterials with a novel mechanism of action offer a great opportunity to combat widespread antimicrobial resistance. Bacterial DNA Gyrase is a clinically validated target. Through physiochemical property optimization of a pyrazolopyridone hit, a novel class of GyrB inhibitors were discovered. Guided by structure-based drug design, indazole derivatives with excellent enzymatic and antibacterial activity as well as great animal efficacy were discovered.
ABSTRACT
The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , DNA Gyrase/metabolism , Indoles/pharmacology , Methicillin-Resistant Staphylococcus aureus/enzymology , Topoisomerase II Inhibitors/pharmacology , Urea/pharmacology , Bacterial Proteins/metabolism , Crystallography, X-Ray , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/enzymology , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/microbiology , Humans , Indoles/chemistry , Methicillin-Resistant Staphylococcus aureus/drug effects , Models, Molecular , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Topoisomerase II Inhibitors/chemistry , Urea/analogs & derivativesABSTRACT
Toll-like receptor 4 (TLR4) induced proinflammatory signaling has been directly implicated in severe sepsis and represents an attractive therapeutic target. Herein, we report our investigations into the structure-activity relationship and preliminary drug metabolism/pharmacokinetics study of ß-amino alcohol derivatives that inhibit the TLR4 signaling pathway. Lead compounds were identified from in vitro cellular examination with micromolar potency for their inhibitory effects on TLR4 signaling and subsequently assessed for their ability to suppress the TLR4-induced inflammatory response in an ex vivo whole blood model. In addition, the toxicology, specificity, solubility, brain-blood barrier permeability, and drug metabolism of several compounds were evaluated. Although further optimizations are needed, our findings lay the groundwork for the future drug development of this class of small molecule agents for the treatment of severe sepsis.
Subject(s)
Amino Alcohols/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Toll-Like Receptor 4/antagonists & inhibitors , Amino Alcohols/pharmacokinetics , Amino Alcohols/pharmacology , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Blood-Brain Barrier/metabolism , Cell Line, Tumor , Humans , In Vitro Techniques , Lipopolysaccharides/pharmacology , Macrophage Activation/drug effects , Mice , Models, Molecular , Nitric Oxide/biosynthesis , Permeability , Sepsis/drug therapy , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Toll-like receptor 4 (TLR4), a membrane spanning receptor protein that functions in complex with its accessory protein MD-2, is an intriguing target for therapeutic development. Herein we report the identification of a series of novel TLR4 inhibitors and the development of a robust, enantioselective synthesis using an unprecedented Mannich-type reaction to functionalize a pyrazole ring. In silico and cellular assay results demonstrated that compound 1 and its analogues selectively block TLR4 activation in live cells. Animal model tests showed that 1 and its derivatives could potentiate morphine-induced analgesia in vivo, presumably by attenuating the opioid-induced TLR4 activation.
