RESUMEN
Derivatives of lactam, cyclic urea and carbamate were explored as aniline amide replacements in a series of phthalazinone-based ROCK inhibitors. Potent ROCK2 inhibitors such as 22 were identified with excellent overall kinase selectivity as well as good isoform selectivity over ROCK1.
Asunto(s)
Amidas , Lactamas , Quinasas Asociadas a rho , Lactamas/farmacología , Isoformas de Proteínas , Quinasas Asociadas a rho/antagonistas & inhibidoresRESUMEN
Agonism of the apelin receptor (APJ) has demonstrated beneficial effects in models of heart failure. We have previously disclosed compounds such as 4, which showed good APJ agonist activity but were metabolized to the mono-demethylated, non-interconverting atropisomer metabolites. Herein, we detail the design and optimization of a novel series of N-linked APJ agonists with good potency, metabolic stability, and rat pharmacokinetic profile, which are unable to undergo the same metabolic mono-demethylation cleavage.
Asunto(s)
Piridinas , Receptores Acoplados a Proteínas G , Animales , Apelina , Receptores de Apelina/agonistas , Ratas , Receptores Acoplados a Proteínas G/agonistasRESUMEN
Heart failure (HF) treatment remains a critical unmet medical need. Studies in normal healthy volunteers and HF patients have shown that [Pyr1]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac function. However, the short half-life of [Pyr1]apelin-13 and the need for intravenous administration have limited the therapeutic potential for chronic use. We sought to identify potent, small-molecule APJ agonists with improved pharmaceutical properties to enable oral dosing in clinical studies. In this manuscript, we describe the identification of a series of pyrimidinone sulfones as a structurally differentiated series to the clinical lead (compound 1). Optimization of the sulfone series for potency, metabolic stability and oral bioavailability led to the identification of compound 22, which showed comparable APJ potency to [Pyr1]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.
Asunto(s)
Receptores de Apelina/agonistas , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/farmacocinética , Péptidos y Proteínas de Señalización Intercelular/farmacología , Animales , Área Bajo la Curva , Fármacos Cardiovasculares/síntesis química , Diseño de Fármacos , Semivida , Humanos , Péptidos y Proteínas de Señalización Intercelular/química , Macaca fascicularis , Estructura Molecular , Pirimidinonas/química , Pirimidinonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design and evaluation of MPO inhibitors for the treatment of cardiovascular disease are reported herein. Starting with the MPO and triazolopyridine 3 crystal structure, novel inhibitors were designed incorporating a substituted pyrazole, which allowed for substituents to interact with hydrophobic and hydrophilic patches in the active site. SAR exploration of the substituted pyrazoles led to piperidine 17, which inhibited HOCl production from activated neutrophils with an IC50 value of 2.4 µM and had selectivity against thyroid peroxidase (TPO). Optimization of alkylation chemistry on the pyrazole nitrogen facilitated the preparation of many analogs, including macrocycles designed to bridge two hydrophobic regions of the active site. Multiple macrocyclization strategies were pursued to prepare analogs that optimally bound to the active site, leading to potent macrocyclic MPO inhibitors with TPO selectivity, such as compound 30.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Compuestos Macrocíclicos/farmacología , Peroxidasa/antagonistas & inhibidores , Pirazoles/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Estructura Molecular , Peroxidasa/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Over the past few decades, drug discovery directed at the treatment and prevention of thromboembolic diseases has been challenged by the need to balance robust efficacy with improved safety relative to the standard of care. To this end, the most impactful advance to date has been the discovery and development of oral factor Xa inhibitors. In this essay, a brief account of the program that culminated in the discovery of Eliquis (apixaban) and the commitment to identify a compound with an optimal profile are described.
Asunto(s)
Descubrimiento de Drogas , Inhibidores del Factor Xa/uso terapéutico , Humanos , Pirazoles , PiridonasRESUMEN
A novel series of 5H-chromeno[3,4-c]pyridine, 6H-isochromeno[3,4-c]pyridine and 6H-isochromeno[4,3-d]pyrimidine derivatives as dual ROCK1 and ROCK2 inhibitors is described. Optimization led to compounds with sub-nanomolar inhibitory affinity for both kinases and excellent kinome selectivity. Compound 19 exhibited ROCK1 and ROCK2 IC50 of 0.67 nM and 0.18 nM respectively.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Relación Estructura-Actividad , Quinasas Asociadas a rho/metabolismoRESUMEN
The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.
Asunto(s)
Aminas/química , Factor XIa/antagonistas & inhibidores , Compuestos Macrocíclicos/química , Inhibidores de Serina Proteinasa/síntesis química , Administración Oral , Animales , Sitios de Unión , Diseño de Fármacos , Factor XIa/metabolismo , Semivida , Compuestos Macrocíclicos/metabolismo , Compuestos Macrocíclicos/farmacocinética , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Piridinas/química , Ratas , Inhibidores de Serina Proteinasa/metabolismo , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-ActividadRESUMEN
This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.
Asunto(s)
Receptores de Apelina/agonistas , Pirimidinonas/farmacología , Descubrimiento de Drogas , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Estructura Molecular , Pirimidinonas/síntesis química , Relación Estructura-ActividadRESUMEN
Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Animales , Presión Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Quinasas Asociadas a rho/metabolismoRESUMEN
Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Peroxidasa/antagonistas & inhibidores , Piridinas/farmacología , Triazoles/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Peroxidasa/metabolismo , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
A series of benzothiazoles with a cyano group was synthesized and evaluated as endothelial lipase (EL) inhibitors for the potential treatment of cardiovascular diseases. Efforts to reduce molecular weight and polarity in the series led to improved physicochemical properties of these compounds, as well as selectivity for EL over hepatic lipase (HL). As a benchmark compound, 8i demonstrated potent EL activity, an acceptable absorption, distribution, metabolism and elimination (ADME) profile and pharmacokinetic (PK) exposure which allowed further evaluation in preclinical animal efficacy studies.
Asunto(s)
Benzotiazoles/química , Enfermedades Cardiovasculares/tratamiento farmacológico , Inhibidores Enzimáticos/química , Lipasa/antagonistas & inhibidores , Animales , Benzotiazoles/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Lipasa/genética , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (Ctroughâ¯>â¯15 fold over mouse plasma EL IC50 over 4â¯days).
RESUMEN
This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.
Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas , Factor XIa/antagonistas & inhibidores , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/química , Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/química , Administración Oral , Disponibilidad Biológica , Humanos , Ligandos , Compuestos Macrocíclicos/farmacología , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability.
Asunto(s)
Factor XIa/antagonistas & inhibidores , Piridazinas/farmacología , Inhibidores de Serina Proteinasa/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Factor XIa/metabolismo , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Piridazinas/síntesis química , Piridazinas/química , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Relación Estructura-ActividadRESUMEN
Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Lipasa/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacología , Animales , HDL-Colesterol/sangre , HDL-Colesterol/metabolismo , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/síntesis química , Humanos , Lipasa/sangre , Lipasa/metabolismo , Ratones , Modelos Moleculares , Pirimidinonas/sangre , Pirimidinonas/síntesis química , Relación Estructura-ActividadRESUMEN
A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay.
Asunto(s)
Factor XIa/antagonistas & inhibidores , Imidazoles/farmacología , Compuestos Macrocíclicos/farmacología , Inhibidores de Serina Proteinasa/farmacología , Relación Dosis-Respuesta a Droga , Factor XIa/metabolismo , Humanos , Imidazoles/síntesis química , Imidazoles/química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Estructura Molecular , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Relación Estructura-ActividadRESUMEN
Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Factor XIa/antagonistas & inhibidores , Compuestos Macrocíclicos/farmacología , Inhibidores de Serina Proteinasa/farmacología , Amidas/síntesis química , Amidas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Factor XIa/metabolismo , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Relación Estructura-ActividadRESUMEN
Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability.
Asunto(s)
Factor VIIa/antagonistas & inhibidores , Compuestos Macrocíclicos/farmacología , Inhibidores de Serina Proteinasa/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Estructura Molecular , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Relación Estructura-ActividadRESUMEN
Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.
Asunto(s)
Factor VIIa/antagonistas & inhibidores , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Tromboplastina/antagonistas & inhibidores , Animales , Perros , Diseño de Fármacos , Humanos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Relación Estructura-ActividadRESUMEN
The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8µM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).