RESUMEN
Early prediction of clearance mechanisms allows for the rapid progression of drug discovery and development programs, and facilitates risk assessment of the pharmacokinetic variability associated with drug interactions and pharmacogenomics. Here we propose a scientific framework--Extended Clearance Classification System (ECCS)--which can be used to predict the predominant clearance mechanism (rate-determining process) based on physicochemical properties and passive membrane permeability. Compounds are classified as: Class 1A--metabolism as primary systemic clearance mechanism (high permeability acids/zwitterions with molecular weight (MW) ≤400 Da), Class 1B--transporter-mediated hepatic uptake as primary systemic clearance mechanism (high permeability acids/zwitterions with MW >400 Da), Class 2--metabolism as primary clearance mechanism (high permeability bases/neutrals), Class 3A--renal clearance (low permeability acids/zwitterions with MW ≤400 Da), Class 3B--transporter mediated hepatic uptake or renal clearance (low permeability acids/zwitterions with MW >400 Da), and Class 4--renal clearance (low permeability bases/neutrals). The performance of the ECCS framework was validated using 307 compounds with single clearance mechanism contributing to ≥70% of systemic clearance. The apparent permeability across clonal cell line of Madin - Darby canine kidney cells, selected for low endogenous efflux transporter expression, with a cut-off of 5 × 10(-6) cm/s was used for permeability classification, and the ionization (at pH7) was assigned based on calculated pKa. The proposed scheme correctly predicted the rate-determining clearance mechanism to be either metabolism, hepatic uptake or renal for ~92% of total compounds. We discuss the general characteristics of each ECCS class, as well as compare and contrast the framework with the biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS). Collectively, the ECCS framework is valuable in early prediction of clearance mechanism and can aid in choosing the right preclinical tool kit and strategy for optimizing drug exposure and evaluating clinical risk of pharmacokinetic variability caused by drug interactions and pharmacogenomics.
Asunto(s)
Descubrimiento de Drogas , Riñón/metabolismo , Hígado/metabolismo , Tasa de Depuración Metabólica , Preparaciones Farmacéuticas/metabolismo , Eliminación Renal , Animales , Línea Celular , Perros , Descubrimiento de Drogas/métodos , Humanos , Modelos Biológicos , Permeabilidad , Preparaciones Farmacéuticas/clasificaciónRESUMEN
To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection of drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against the virus Mpro inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six Mpro mutation patterns containing T304I alone or in combination with T21I, L50F, T135I, S144A, or A173V emerged, with A173V+T304I and T21I+S144A+T304I mutations showing >20-fold resistance each. Biochemical analyses indicated inhibition constant shifts aligned to antiviral results, with S144A and A173V each markedly reducing nirmatrelvir inhibition and Mpro activity. SARS-CoV-2 surveillance revealed that in vitro resistance-associated mutations from our studies and those reported in the literature were rarely detected in the Global Initiative on Sharing All Influenza Data database. In the Paxlovid Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients trial, E166V was the only emergent resistance mutation, observed in three Paxlovid-treated patients, none of whom experienced COVID-19-related hospitalization or death.
Asunto(s)
Antivirales , Tratamiento Farmacológico de COVID-19 , Farmacorresistencia Viral , Mutación , SARS-CoV-2 , SARS-CoV-2/genética , SARS-CoV-2/efectos de los fármacos , Farmacorresistencia Viral/genética , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/virología , COVID-19/genética , COVID-19/epidemiología , Proteasas 3C de Coronavirus/genética , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Lactamas , Leucina , Nitrilos , ProlinaRESUMEN
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.
Asunto(s)
Antivirales , Tratamiento Farmacológico de COVID-19 , Inhibidores de Proteasas , SARS-CoV-2 , Humanos , Animales , Ratones , SARS-CoV-2/efectos de los fármacos , Antivirales/farmacología , Antivirales/farmacocinética , Antivirales/uso terapéutico , Antivirales/química , Administración Oral , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Inhibidores de Proteasas/química , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Ratas , COVID-19/virologíaRESUMEN
Successful small-molecule drug design requires a molecular target with inherent therapeutic potential and a molecule with the right properties to unlock its potential. Present-day drug design strategies have evolved to leave little room for improvement in drug-like properties. As a result, inadequate safety or efficacy associated with molecular targets now constitutes the primary cause of attrition in preclinical development through Phase II. This finding has led to a deeper focus on target selection. In this current reality, design tactics that enable rapid identification of risk-balanced clinical candidates, translation of clinical experience into meaningful differentiation strategies, and expansion of the druggable proteome represent significant levers by which drug designers can accelerate the discovery of the next generation of medicines.
Asunto(s)
Diseño de FármacosRESUMEN
The pharmaceutical industry has faced declining research and development (R&D) productivity for decades. During the early 2010s, Pfizer saw its R&D productivity drop even more sharply than did its industry peers. As impactful medicines the company had developed and brought to patients in previous years lost exclusivity, Pfizer faced a steep patent cliff with a cumulative revenue impact of >US$28 billion through 2018. Since 2010, the company has embarked on a focused turnaround effort to improve R&D productivity. Although some efforts will need more time to prove themselves, there are early signs of a turnaround now, particularly in terms of Phase II success rates. Here, we share some learnings from a decade of experience as one of the largest R&D organizations in the industry.
Asunto(s)
Desarrollo de Medicamentos/tendencias , Industria Farmacéutica/tendencias , Investigación/tendencias , Desarrollo de Medicamentos/economía , Desarrollo de Medicamentos/organización & administración , Industria Farmacéutica/economía , Industria Farmacéutica/organización & administración , Eficiencia Organizacional , Humanos , Investigación/economía , Investigación/organización & administraciónRESUMEN
Innovation has a crucial role in developing breakthrough drugs and vaccines that can change patients' lives. To better understand this role, we evaluated recent outcomes for assets developed using different types of innovation. Although all approaches have delivered breakthroughs, assets that modulate established biological targets with innovative scientific or technological designs provide a unique combination of reduced development risk, high patient impact, and high commercial value. This type of asset currently represents a relatively small proportion of approved drugs and vaccines, but we anticipate that an increasing body of scientific knowledge and ongoing technological advancements could offer opportunities to grow this category in the future.
Asunto(s)
Desarrollo de Medicamentos/métodos , Vacunas/administración & dosificación , Aprobación de Drogas , Desarrollo de Medicamentos/tendencias , Humanos , Invenciones , Riesgo , Tecnología/tendenciasRESUMEN
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro , and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.
RESUMEN
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Lactamas/farmacología , Lactamas/uso terapéutico , Leucina/farmacología , Leucina/uso terapéutico , Nitrilos/farmacología , Nitrilos/uso terapéutico , Prolina/farmacología , Prolina/uso terapéutico , SARS-CoV-2/efectos de los fármacos , Inhibidores de Proteasa Viral/farmacología , Inhibidores de Proteasa Viral/uso terapéutico , Administración Oral , Animales , COVID-19/virología , Ensayos Clínicos Fase I como Asunto , Coronavirus/efectos de los fármacos , Modelos Animales de Enfermedad , Quimioterapia Combinada , Humanos , Lactamas/administración & dosificación , Lactamas/farmacocinética , Leucina/administración & dosificación , Leucina/farmacocinética , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Nitrilos/administración & dosificación , Nitrilos/farmacocinética , Prolina/administración & dosificación , Prolina/farmacocinética , Ensayos Clínicos Controlados Aleatorios como Asunto , Ritonavir/administración & dosificación , Ritonavir/uso terapéutico , SARS-CoV-2/fisiología , Inhibidores de Proteasa Viral/administración & dosificación , Inhibidores de Proteasa Viral/farmacocinética , Replicación Viral/efectos de los fármacosRESUMEN
This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.
Asunto(s)
Pirimidinonas/química , Pirimidinonas/uso terapéutico , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/uso terapéutico , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Humanos , Pirimidinonas/farmacología , Receptor de Serotonina 5-HT2B/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-Actividad , Uretra/efectos de los fármacos , Incontinencia Urinaria/tratamiento farmacológicoRESUMEN
The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.
Asunto(s)
Piperazinas/síntesis química , Piridazinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/síntesis química , Animales , Perros , Diseño de Fármacos , Humanos , Piperazinas/química , Piperazinas/farmacología , Piridazinas/química , Piridazinas/farmacocinética , Piridazinas/farmacología , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacocinética , Relación Estructura-Actividad , Incontinencia Urinaria de Esfuerzo/tratamiento farmacológicoRESUMEN
Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.
Asunto(s)
Aminoácidos/síntesis química , Fibrinólisis/efectos de los fármacos , Fibrinolíticos/síntesis química , Imidazoles/síntesis química , Trombina/metabolismo , Aminoácidos/farmacocinética , Aminoácidos/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Pérdida de Sangre Quirúrgica/prevención & control , Carboxipeptidasa B/química , Dominio Catalítico , Cristalografía por Rayos X , Perros , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacología , Semivida , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Masculino , Modelos Moleculares , Estructura Molecular , Páncreas/enzimología , Conejos , Estereoisomerismo , Relación Estructura-Actividad , Porcinos , Tromboembolia Venosa/tratamiento farmacológicoRESUMEN
This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
Asunto(s)
Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/síntesis química , Diseño de Fármacos , Receptores de Dopamina D3/agonistas , Administración Intranasal , Animales , Cristalografía por Rayos X , Perros , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacocinética , Humanos , Modelos Moleculares , Estructura Molecular , Ratas , Receptores de Dopamina D3/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Azetidinas/síntesis química , Pirimidinas/síntesis química , Pirimidinonas/síntesis química , 3',5'-GMP Cíclico Fosfodiesterasas/química , Administración Oral , Animales , Azetidinas/química , Azetidinas/farmacología , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Perros , Relación Dosis-Respuesta a Droga , Disfunción Eréctil/tratamiento farmacológico , Humanos , Cetonas/química , Masculino , Modelos Moleculares , Estructura Molecular , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Relación Estructura-ActividadRESUMEN
The SAR of a series of beta-carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE5 potency and selectivity over PDE6. However, the series exhibits low levels of selectivity over PDE11, a phosphodiesterase with unknown function.