ABSTRACT
Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.
ABSTRACT
Prostaglandin E receptor subtype 3 (EP3) antagonism may treat a variety of symptoms from inflammation to cardiovascular and metabolic diseases. Previously, most EP3 antagonists were large acidic ligands that mimic the substrate, prostaglandin E2 (PGE2). This manuscript describes the optimization of a neutral small molecule amide series with improved lipophilic efficiency (LipE) also known as lipophilic ligand efficiency (LLE) ((a) Nat. Rev. Drug Disc.2007, 6, 881; (b) Annu. Rep. Med. Chem.2010, 45, 380).
Subject(s)
Amides/pharmacology , Receptors, Prostaglandin E, EP3 Subtype/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synthetase (LysRS). Preliminary structure-activity relationship (SAR) studies led to an analog, PPD-2, which gained Gram-negative antibacterial activity at the expense of MRSA activity and resistance to this compound mapped to prolyl tRNA synthetase (ProRS). These targets of inhibition were confirmed in vitro, with PPD-1 showing IC50s of 21.7 and 35 µM in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04 µM, respectively. The highly attractive chemical properties of these compounds combined with intriguing preliminary SAR suggest that further exploration of this compelling novel series is warranted.
Subject(s)
Amino Acyl-tRNA Synthetases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Drug Design , Drug Discovery , Pyrazoles/pharmacology , Pyrimidinones/pharmacology , Amino Acyl-tRNA Synthetases/genetics , Amino Acyl-tRNA Synthetases/metabolism , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Drug Resistance, Bacterial , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Escherichia coli/enzymology , Escherichia coli/growth & development , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , High-Throughput Screening Assays , Lysine-tRNA Ligase/antagonists & inhibitors , Lysine-tRNA Ligase/genetics , Lysine-tRNA Ligase/metabolism , Methicillin Resistance , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/enzymology , Methicillin-Resistant Staphylococcus aureus/growth & development , Microbial Sensitivity Tests , Neisseria gonorrhoeae/drug effects , Neisseria gonorrhoeae/enzymology , Neisseria gonorrhoeae/growth & development , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Pseudomonas aeruginosa/growth & development , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Structure-Activity Relationship , Transfer RNA Aminoacylation/drug effectsABSTRACT
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
Subject(s)
Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Monobactams/pharmacology , Pyridones/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Escherichia coli/drug effects , Inhibitory Concentration 50 , Klebsiella pneumoniae/drug effects , Male , Microbial Sensitivity Tests , Molecular Structure , Monobactams/chemistry , Monobactams/pharmacokinetics , Pseudomonas aeruginosa/drug effects , Pyridones/chemistry , Pyridones/pharmacokinetics , Rats , Rats, WistarABSTRACT
The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Discovery , Neoplasms/drug therapy , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Receptor, TIE-2/antagonists & inhibitors , Animals , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Male , Molecular Structure , Neoplasms/enzymology , Neoplasms/pathology , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Rats , Rats, Sprague-Dawley , Receptor, TIE-2/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
Subject(s)
Drug Resistance, Multiple, Bacterial/drug effects , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Monobactams/pharmacology , Animals , Binding Sites/drug effects , Blood Proteins/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Gram-Negative Bacterial Infections/microbiology , Humans , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Monobactams/chemical synthesis , Monobactams/chemistry , Rats , Structure-Activity RelationshipABSTRACT
The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Hydroxamic Acids/chemical synthesis , Pyridones/chemical synthesis , Sulfonic Acids/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Crystallography, X-Ray , Humans , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Protein Conformation , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Pyridones/pharmacokinetics , Pyridones/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfonic Acids/pharmacokinetics , Sulfonic Acids/pharmacologyABSTRACT
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Hydroxamic Acids/chemical synthesis , Phenyl Ethers/chemical synthesis , Pseudomonas Infections/drug therapy , Sulfides/chemical synthesis , Sulfones/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Catalytic Domain , Crystallography, X-Ray , Drug Resistance, Bacterial , Hydrogen Bonding , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Mice , Models, Molecular , Molecular Conformation , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacology , Pseudomonas aeruginosa , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfides/chemistry , Sulfides/pharmacology , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
An efficient method was developed for the synthesis of 2-methylene-4-substituted ethyl butyrates via cyclopropyl opening followed by a Wittig reaction. The desired products were formed in a two-step, one-pot reaction sequence. Alternatively, the key intermediate ylide 2 was isolable and could be stored under oxygen-free conditions and subsequently utilized. A variety of nucleophiles were found to open the commercially available cyclopropane 1. The resulting ylide reacted with aldehydes to provide E-olefinic products.
Subject(s)
Borates/chemistry , Organophosphorus Compounds/chemistry , Aldehydes/chemistry , Cyclization , Molecular StructureABSTRACT
The Aurora family of highly related serine/threonine kinases plays a key role in the regulation of mitosis. Aurora1 and Aurora2 play important but distinct roles in the G(2) and M phases of the cell cycle and are essential for proper chromosome segregation and cell division. Overexpression and amplification of Aurora2 have been reported in different tumor types, including breast, colon, pancreatic, ovarian, and gastric cancer. PF-03814735 is a novel, potent, orally bioavailable, reversible inhibitor of both Aurora1 and Aurora2 kinases that is currently in phase I clinical trials for the treatment of advanced solid tumors. In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. Although PF-03814735 produces significant inhibition of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases. Once-daily oral administration of PF-03814735 to mice bearing human xenograft tumors produces a reduction in phosphohistone H3 in tumors at doses that are tolerable and that result in significant inhibition of tumor growth. The combination of PF-03814735 and docetaxel in xenograft mouse tumor models shows additive tumor growth inhibition. These results support the clinical evaluation of PF-03814735 in cancer patients. Mol Cancer Ther; 9(4); 883-94. (c)2010 AACR.
Subject(s)
Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/therapeutic use , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Administration, Oral , Animals , Aurora Kinases , Biological Availability , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/pharmacology , Histones/metabolism , Humans , Mice , Mice, Nude , Neoplasms/pathology , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Substrate Specificity/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The synthesis and biological evaluation of potent and selective inhibitors of the erbB2 kinase is presented. Based on the 4-anilinoquinazoline chemotype, the syntheses of several new series of erbB2 inhibitors are described with quinazoline and pyrido[4,3-d]pyrimidine cores. The vast majority of these compounds are found to be >100x selective over the closely related EGFR kinase. Two lead compounds are further shown to have low clearance and moderate bioavailability in rat.
