RESUMEN
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
The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 °C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.
RESUMEN
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
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.
Asunto(s)
Agonistas del Receptor de Adenosina A2 , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Adenosina/análogos & derivados , Adenosina/química , Administración por Inhalación , Adolescente , Adulto , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Pulmón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Modelos Químicos , Fenetilaminas/química , Purinas/química , Ratas , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K(i) in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Electromiografía/métodos , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Ratas , Receptores de Glutamato Metabotrópico/fisiología , Relación Estructura-ActividadRESUMEN
A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective delta-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure-activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series.
Asunto(s)
4-Aminopiridina/análogos & derivados , Química Farmacéutica/métodos , Canales de Potasio Éter-A-Go-Go/química , Receptores Opioides delta/agonistas , 4-Aminopiridina/síntesis química , 4-Aminopiridina/farmacología , Analgésicos Opioides/farmacología , Animales , Línea Celular , Técnicas Químicas Combinatorias , Diseño de Fármacos , Canal de Potasio ERG1 , Electromiografía/métodos , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Modelos Químicos , Ratas , Receptores Opioides delta/química , Relación Estructura-ActividadRESUMEN
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.
Asunto(s)
Agonistas del Receptor de Adenosina A2 , Adenosina/análogos & derivados , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Adenosina/farmacocinética , Adenosina/farmacología , Administración por Inhalación , Administración Oral , Aminas/farmacocinética , Aminas/farmacología , Animales , Cobayas , Humanos , Pulmón/metabolismo , Fenetilaminas/farmacocinética , Fenetilaminas/farmacología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A strategy has been developed for a rapid seven-step construction of a chiral, nonracemic vinyl cyclopentanone building block as part of a synthetic approach to viridenomycin, using a diastereo- and enantioselective Mukaiyama aldol and intramolecular Knoevenagel condensation as key steps.
Asunto(s)
Aldehídos/química , Ciclopentanos/química , Lactamas/síntesis química , EstereoisomerismoRESUMEN
A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability.
Asunto(s)
Dolor/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Unión Competitiva/efectos de los fármacos , Células CHO , Fenómenos Químicos , Química Física , Enfermedad Crónica , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Ácido Glutámico/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)
Asunto(s)
Ácidos Carbocíclicos/síntesis química , Amidas/síntesis química , Neprilisina/antagonistas & inhibidores , Ácidos Pentanoicos/síntesis química , Disfunciones Sexuales Psicológicas/tratamiento farmacológico , Tiadiazoles/síntesis química , Ácidos Carbocíclicos/farmacocinética , Ácidos Carbocíclicos/farmacología , Amidas/farmacocinética , Amidas/farmacología , Animales , Células CHO , Clítoris/irrigación sanguínea , Clítoris/efectos de los fármacos , Cricetinae , Cricetulus , Perros , Femenino , Humanos , Masculino , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacología , Piridinas/síntesis química , Piridinas/farmacocinética , Piridinas/farmacología , Conejos , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Flujo Sanguíneo Regional/efectos de los fármacos , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/farmacocinética , Tiadiazoles/farmacología , Vagina/irrigación sanguínea , Vagina/efectos de los fármacosRESUMEN
A novel series of small molecule inhibitors of IgE synthesis are described. Compounds were optimized for potency, metabolic stability and absence of genetic toxicology.
Asunto(s)
Inmunoglobulina E/biosíntesis , Compuestos Orgánicos/química , Compuestos Orgánicos/farmacología , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Humanos , Inmunoglobulina E/inmunología , Concentración 50 Inhibidora , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Estructura Molecular , Peso MolecularRESUMEN
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
A series of small molecule glutaramides were synthesized and evaluated for potency against canine and human neutral endopeptidase using target criteria of molecular weight <400 and log P between 2 and 4.5 to maximize the likelihood of achieving good oral absorption. The structure-activity relationship (SAR) investigations described in this paper led to the identification of an ethyl 1,3,4-thiadiazole glutaramide which demonstrated good neutral endopeptidase potency, selectivity and excellent oral absorption in the rat.
Asunto(s)
Amidas/síntesis química , Inhibidores Enzimáticos/química , Ácidos Pentanoicos/síntesis química , Tiadiazoles/síntesis química , Administración Oral , Amidas/química , Amidas/farmacocinética , Animales , Ácidos Ciclohexanocarboxílicos/química , Perros , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Peso Molecular , Neprilisina/metabolismo , Ácidos Pentanoicos/química , Ácidos Pentanoicos/metabolismo , Ácidos Pentanoicos/farmacología , Inhibidores de Proteasas/química , Ratas , Disfunciones Sexuales Psicológicas/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/metabolismo , Tiadiazoles/farmacologíaRESUMEN
A series of zwitterionic delta-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and kappa-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog pharmacokinetic studies on 3a indicated encouraging oral bioavailability.
Asunto(s)
Indoles/farmacología , Isoquinolinas/farmacología , Receptores Opioides delta/agonistas , Animales , Perros , Diseño de Fármacos , Indoles/administración & dosificación , Indoles/síntesis química , Isoquinolinas/administración & dosificación , Isoquinolinas/síntesis química , Ratones , Conformación Molecular , Peso Molecular , 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.