RESUMEN
The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7/química , Piperidinas/química , Piridinas/química , Sulfonamidas/química , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Animales , Sitios de Unión , Perros , Semivida , Hepatocitos/metabolismo , Humanos , Infusiones Intravenosas , Concentración 50 Inhibidora , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Dolor/tratamiento farmacológico , Dolor/patología , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Unión Proteica , Estructura Terciaria de Proteína , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Tiadiazoles , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinética , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéuticoRESUMEN
This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacocinética , Pirimidinonas/química , Pirimidinonas/farmacocinética , Sulfonamidas/química , Sulfonamidas/farmacocinética , Administración Oral , Disponibilidad Biológica , Línea Celular , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Humanos , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Síntomas del Sistema Urinario Inferior/etiología , Masculino , Inhibidores de Fosfodiesterasa 5/farmacología , Hiperplasia Prostática/complicaciones , Pirimidinonas/farmacología , Sulfonamidas/farmacologíaRESUMEN
A potent series of substituted (2S,4S)-benzylproline α(2)δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-L-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development.
Asunto(s)
Diseño de Fármacos , Prolina/química , Prolina/síntesis química , Animales , Humanos , Concentración 50 Inhibidora , Ligandos , Estructura Molecular , Dolor , Prolina/farmacología , Ratas , PorcinosRESUMEN
Conformational constraint has been used to design a potent series of α(2)δ ligands derived from the readily available starting material (2S,4R)-hydroxy-l-proline. The ligands have improved physicochemistry and potency compared to their linear counterparts (described in our earlier publication) and the lead compound has been progressed to clinical development.
Asunto(s)
Diseño de Fármacos , Hidroxiprolina/síntesis química , Aminas/química , Aminas/farmacocinética , Animales , Células Cultivadas , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Perros , Gabapentina , Humanos , Hidroxiprolina/química , Ligandos , Estructura Molecular , Subunidades de Proteína/química , Ratas , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
A new series of glycine-derived ligands of the α(2)δ subunit of voltage gated calcium channels is described. Several novel compounds (7) based on (6) were prepared that possessed a potency <100 nM in the α(2)δ binding assay.
Asunto(s)
Canales de Calcio/efectos de los fármacos , Glicina/síntesis química , Ligandos , Alquilación , Glicina/química , Glicina/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Subunidades de Proteína/química , Relación Estructura-ActividadRESUMEN
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Éteres Fenílicos/farmacología , Sulfonamidas/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Línea Celular , Citocromo P-450 CYP2C9/metabolismo , Inhibidores del Citocromo P-450 CYP2C9/síntesis química , Inhibidores del Citocromo P-450 CYP2C9/química , Inhibidores del Citocromo P-450 CYP2C9/farmacocinética , Inhibidores del Citocromo P-450 CYP2C9/farmacología , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/síntesis química , Inhibidores del Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Diseño de Fármacos , Humanos , Microsomas Hepáticos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.7/química , Éteres Fenílicos/síntesis química , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Bloqueadores del Canal de Sodio Activado por Voltaje/síntesis química , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinéticaRESUMEN
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
Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.
RESUMEN
Conformational constraint has been used as the key design element in the identification of a series of potent and selective ET(A) antagonists. The most potent antagonist, 32, (ET(A) IC(50)=0.55nM) is 722-fold selective over the ET(B) receptor, as measured by binding experiments.