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1.
J Med Chem ; 67(12): 10248-10262, 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38848667

RESUMEN

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aß42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid ß (Aß) 42 in cerebrospinal fluid (CSF).


Asunto(s)
Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Animales , Péptidos beta-Amiloides/metabolismo , Ratas , Relación Estructura-Actividad , Ratones , Masculino , Descubrimiento de Drogas , Furanos/farmacología , Furanos/farmacocinética , Furanos/síntesis química , Furanos/química , Furanos/uso terapéutico , Ratas Sprague-Dawley , Encéfalo/metabolismo
2.
J Med Chem ; 67(16): 13550-13571, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-38687966

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.


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/virología
3.
Drug Metab Dispos ; 50(5): 576-590, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35153195

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (Paxlovid), was recently granted emergency use authorization by multiple regulatory agencies for the treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients. Disposition studies on nirmatrelvir in animals and in human reagents, which were used to support clinical studies, are described herein. Plasma clearance was moderate in rats (27.2 ml/min per kg) and monkeys (17.1 ml/min per kg), resulting in half-lives of 5.1 and 0.8 hours, respectively. The corresponding oral bioavailability was moderate in rats (34%-50%) and low in monkeys (8.5%), primarily due to oxidative metabolism along the gastrointestinal tract in this species. Nirmatrelvir demonstrated moderate plasma protein binding in rats, monkeys, and humans with mean unbound fractions ranging from 0.310 to 0.478. The metabolism of nirmatrelvir was qualitatively similar in liver microsomes and hepatocytes from rats, monkeys, and humans; prominent metabolites arose via cytochrome P450 (CYP450)-mediated oxidations on the P1 pyrrolidinone ring, P2 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, and the tertiary-butyl group at the P3 position. Reaction phenotyping studies in human liver microsomes revealed that CYP3A4 was primarily responsible (fraction metabolized = 0.99) for the oxidative metabolism of nirmatrelvir. Minor clearance mechanisms involving renal and biliary excretion of unchanged nirmatrelvir were also noted in animals and in sandwich-cultured human hepatocytes. Nirmatrelvir was a reversible and time-dependent inhibitor as well as inducer of CYP3A activity in vitro. First-in-human pharmacokinetic studies have demonstrated a considerable boost in the oral systemic exposure of nirmatrelvir upon coadministration with the CYP3A4 inhibitor ritonavir, consistent with the predominant role of CYP3A4 in nirmatrelvir metabolism. SIGNIFICANCE STATEMENT: The manuscript describes the preclinical disposition, metabolism, and drug-drug interaction potential of PF-07321332 (nirmatrelvir), an orally active peptidomimetic-based inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease, which has been granted emergency use authorization by multiple regulatory agencies around the globe for the treatment of coronavirus disease 2019 (COVID-19) in COVID-19-positive adults and pediatric patients who are at high risk for progression to severe COVID-19, including hospitalization or death.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Administración Oral , Animales , Niño , Citocromo P-450 CYP3A/metabolismo , Haplorrinos , Humanos , Lactamas , Leucina , Microsomas Hepáticos/metabolismo , Nitrilos , Péptido Hidrolasas/metabolismo , Prolina , Ratas , Ritonavir/metabolismo
4.
Science ; 374(6575): 1586-1593, 2021 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-34726479

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 fármacos
5.
ACS Chem Neurosci ; 12(6): 1007-1017, 2021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33651587

RESUMEN

One of the objectives within the medicinal chemistry discipline is to design tissue targeting molecules. The objective of tissue specificity can be either to gain drug access to the compartment of interest (e.g., the CNS) for Neuroscience targets or to restrict drug access to the CNS for all other therapeutic areas. Both neuroscience and non-neuroscience therapeutic areas have struggled to quantitatively estimate brain penetration or the lack thereof with compounds that are substrates of efflux transport proteins such as P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) that are key components of the blood-brain barrier (BBB). It has been well established that drug candidates with high efflux ratios (ER) of these transporters have poor penetration into brain tissue. In the current work, we outline a parallel analysis to previously published models for the prediction of brain penetration that utilize an alternate MDR1-MDCK cell line as a better predictor of brain penetration and whether a correlation between in vitro, rodent data, non-human primate (NHP), and human in vivo brain penetration data could be established. Analysis of structural and physicochemical properties in conjunction with in vitro parameters and preclinical in vivo data has been highlighted in this manuscript as a continuation of the previously published work.


Asunto(s)
Encéfalo , Proteínas de Neoplasias , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Perros , Humanos , Células de Riñón Canino Madin Darby , Proteínas de Neoplasias/metabolismo
6.
Bioorg Med Chem Lett ; 30(23): 127503, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32853684

RESUMEN

Among the most devastating disorders of our time, neurologic and psychiatric diseases combine to cause more disability than any other disease area. One of the key objectives within the medicinal chemistry discipline is to design molecules that penetrate into the target tissue. The objective of tissue specificity can be to gain or restrict drug access to the compartment of interest. This article briefly reviews the progress of CNS drug discovery over the past few decades. Included are the most recent efforts to harness structural and physicochemical properties assessment coupled with the impact of efflux transporters in determining brain penetration and the translation from rodent to human brain tissue targeting.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Fármacos del Sistema Nervioso Central/metabolismo , Animales , Línea Celular , Descubrimiento de Drogas , Humanos
7.
J Pharm Sci ; 108(7): 2476-2483, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30794795

RESUMEN

It is of great challenge to predict human brain penetration for substrates of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), 2 major efflux transporters at blood-brain barrier. Thus, a physiologically based pharmacokinetic (PBPK) model with the incorporation of in vitro MDR1 and BCRP transporter function data and transporter protein expression levels has been developed. As such, it is crucial to generate MDR1 and BCRP substrate data with a high fidelity. In this study, 2 widely used human MDR1 cell lines from Borst and National Institutes of Health laboratories were evaluated using rodent brain penetration data, and the study suggested that the MDR1 expressed in Madin-Darby canine kidney (MDCK) cell line from National Institutes of Health laboratory predicted brain penetration better, particularly for compounds with a high passive permeability. In addition, human BCRP-MDCK cell line with 1 µM PSC833, a specific MDR1 inhibitor, demonstrated the ability to identify BCRP substrates without the confounding of endogenous canine Mdr1. Comparison of human BCRP and mouse Bcrp transporter functions revealed that the functional differences of BCRP between the 2 species is minimal. The incorporation of both the validated MDR1 and BCRP assays into our brain PBPK model has significantly improved the prediction for the brain penetration of MDR1 and BCRP substrates across species.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transporte Biológico/fisiología , Encéfalo/metabolismo , Proteínas de Neoplasias/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Línea Celular , Perros , Humanos , Células de Riñón Canino Madin Darby , Ratones
8.
Drug Metab Dispos ; 47(4): 405-411, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30683809

RESUMEN

Understanding the quantitative implications of P-glycoprotein and breast cancer resistance protein efflux is a key hurdle in the design of effective, centrally acting or centrally restricted therapeutics. Previously, a comprehensive physiologically based pharmacokinetic model was developed to describe the in vivo unbound brain-to-plasma concentration ratio as a function of efflux activity measured in vitro. In the present work, the predictive utility of this framework was examined through application to in vitro and in vivo data generated on 133 unique compounds across three preclinical species. Two approaches were examined for the scaling of efflux activity to in vivo, namely relative expression as determined by independent proteomics measurements and relative activity as determined via fitting the in vivo neuropharmacokinetic data. The results with both approaches indicate that in vitro efflux data can be used to accurately predict the degree of brain penetration across species within the context of the proposed physiologically based pharmacokinetic framework.


Asunto(s)
Transporte Biológico/fisiología , Barrera Hematoencefálica/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Encéfalo/metabolismo , Línea Celular , Perros , Células de Riñón Canino Madin Darby , Ratas , Ratas Sprague-Dawley
9.
J Med Chem ; 60(20): 8538-8551, 2017 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-28957634

RESUMEN

As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (Bmax) and biodistribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study. In subsequent non-human primate (NHP) PET imaging studies, [18F]8 showed rapid brain uptake and high target specificity, indicating that [18F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inhibidores de Fosfodiesterasa/metabolismo , Tomografía de Emisión de Positrones/métodos , Animales , Corteza Cerebral/metabolismo , Cromatografía Liquida , Descubrimiento de Drogas , Macaca fascicularis , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Espectrometría de Masas en Tándem
10.
J Med Chem ; 58(10): 4291-308, 2015 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-25905800

RESUMEN

A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Receptores AMPA/metabolismo , Sulfonamidas/farmacología , Tiofenos/farmacología , Administración Oral , Adolescente , Adulto , Anciano , Animales , Sitios de Unión , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Estabilidad de Medicamentos , Femenino , Humanos , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones Endogámicos C57BL , Persona de Mediana Edad , Conformación Proteica , Ratas Sprague-Dawley , Esquizofrenia/tratamiento farmacológico , Relación Estructura-Actividad , Sulfonamidas/química , Tiofenos/química , Adulto Joven
11.
J Med Chem ; 56(22): 9180-91, 2013 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-24215237

RESUMEN

Positive allosteric modulators ("potentiators") of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.


Asunto(s)
Descubrimiento de Drogas , Isoxazoles/química , Isoxazoles/farmacología , Receptores AMPA/metabolismo , Absorción , Regulación Alostérica/efectos de los fármacos , Animales , Ensayos Analíticos de Alto Rendimiento , Humanos , Isoxazoles/metabolismo , Isoxazoles/farmacocinética , Masculino , Ratones , Modelos Moleculares , Estructura Terciaria de Proteína , Ratas , Receptores AMPA/química , Relación Estructura-Actividad
12.
Bioorg Med Chem Lett ; 23(10): 3059-63, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23566514

RESUMEN

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 Xenoinjerto
13.
Expert Opin Ther Pat ; 21(2): 205-26, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21231889

RESUMEN

INTRODUCTION: The amyloid precursor protein is first cleaved by ß-secretase to generate a 99-residue membrane-bound CTF (C99 or ß-CTF), which is subsequently cleaved by γ-secretase to generate amyloid ß (Aß) peptides and the APP intracellular domain. The amyloidogenic Aß42 has attracted considerable attention because it is thought to be the most pathogenic species associated with Alzheimer's disease progression. New classes of compounds, called γ-secretase modulators (GSMs), have been shown to selectively lower Aß42 production without shutting down key γ-secretase-dependent signaling pathways. This has become an important therapeutic strategy aimed at modulating Aß production. AREAS COVERED: The progress on the clinical development of γ-secretase inhibitors is briefly covered in this review, followed by a discussion of the potential differentiating attributes of GSMs. Then, the patent literature covering novel GSMs is reviewed, focusing on patents from 2008 to 2010. EXPERT OPINION: Much progress has been made in the past 2 years on developing GSMs with improved potency for lowering the production of Aß42. However, many of these chemotypes are in a challenging chemical space and generally possess higher lipophilicity than most CNS drugs. It will be important to gain a better understanding of the specific target(s) that these GSMs interact with in order to facilitate future drug design efforts.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/efectos de los fármacos , Patentes como Asunto , Inhibidores de Proteasas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Antiinflamatorios no Esteroideos/farmacología , Humanos , Relación Estructura-Actividad
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