RESUMEN
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.
RESUMEN
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).
Asunto(s)
Amidas/farmacología , Subtipo EP3 de Receptores de Prostaglandina E/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Diseño de Fármacos , Descubrimiento de Drogas , Pirazoles/farmacología , Pirimidinonas/farmacología , Aminoacil-ARNt Sintetasas/genética , Aminoacil-ARNt Sintetasas/metabolismo , Antibacterianos/síntesis química , Antibacterianos/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Farmacorresistencia Bacteriana , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Escherichia coli/crecimiento & desarrollo , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Ensayos Analíticos de Alto Rendimiento , Lisina-ARNt Ligasa/antagonistas & inhibidores , Lisina-ARNt Ligasa/genética , Lisina-ARNt Ligasa/metabolismo , Resistencia a la Meticilina , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/enzimología , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Neisseria gonorrhoeae/efectos de los fármacos , Neisseria gonorrhoeae/enzimología , Neisseria gonorrhoeae/crecimiento & desarrollo , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/crecimiento & desarrollo , Pirazoles/síntesis química , Pirazoles/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Aminoacilación de ARN de Transferencia/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Monobactamas/farmacología , Piridonas/farmacología , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Escherichia coli/efectos de los fármacos , Concentración 50 Inhibidora , Klebsiella pneumoniae/efectos de los fármacos , Masculino , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Monobactamas/química , Monobactamas/farmacocinética , Pseudomonas aeruginosa/efectos de los fármacos , Piridonas/química , Piridonas/farmacocinética , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Receptor TIE-2/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Estructura Molecular , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Ratas , Ratas Sprague-Dawley , Receptor TIE-2/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
Asunto(s)
Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Monobactamas/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Proteínas Sanguíneas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Monobactamas/síntesis química , Monobactamas/química , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Compuestos de Bifenilo/síntesis química , Ácidos Hidroxámicos/síntesis química , Éteres Fenílicos/síntesis química , Infecciones por Pseudomonas/tratamiento farmacológico , Sulfuros/síntesis química , Sulfonas/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Dominio Catalítico , Cristalografía por Rayos X , Farmacorresistencia Bacteriana , Enlace de Hidrógeno , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Pseudomonas aeruginosa , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacología , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
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.