RESUMEN
A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/síntesis química , Broncodilatadores/síntesis química , Antagonistas Muscarínicos/síntesis química , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Triazoles/síntesis química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Animales , Disponibilidad Biológica , Broncoconstricción/efectos de los fármacos , Broncodilatadores/farmacocinética , Broncodilatadores/farmacología , Células CHO , Cricetulus , Perros , Humanos , Ipratropio/farmacología , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacología , Ratas , Receptor Muscarínico M3/antagonistas & inhibidores , Xinafoato de Salmeterol/farmacología , Bromuro de Tiotropio/farmacología , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
The transient receptor potential (subfamily M, member 8; TRPM8) is a nonselective cation channel localized in primary sensory neurons, and is a candidate for cold thermosensing, mediation of cold pain, and bladder overactivity. Studies with TRPM8 knockout mice and selective TRPM8 channel blockers demonstrate a lack of cold sensitivity and reduced cold pain in various rodent models. Furthermore, TRPM8 blockers significantly lower body temperature. We have identified a moderately potent (IC50 = 103 nM), selective TRPM8 antagonist, PF-05105679 [(R)-3-[(1-(4-fluorophenyl)ethyl)(quinolin-3-ylcarbonyl)amino]methylbenzoic acid]. It demonstrated activity in vivo in the guinea pig bladder ice water and menthol challenge tests with an IC50 of 200 nM and reduced core body temperature in the rat (at concentrations >1219 nM). PF-05105679 was suitable for acute administration to humans and was evaluated for effects on core body temperature and experimentally induced cold pain, using the cold pressor test. Unbound plasma concentrations greater than the IC50 were achieved with 600- and 900-mg doses. The compound displayed a significant inhibition of pain in the cold pressor test, with efficacy equivalent to oxycodone (20 mg) at 1.5 hours postdose. No effect on core body temperature was observed. An unexpected adverse event (hot feeling) was reported, predominantly periorally, in 23 and 36% of volunteers (600- and 900-mg dose, respectively), which in two volunteers was nontolerable. In conclusion, this study supports a role for TRPM8 in acute cold pain signaling at doses that do not cause hypothermia.
Asunto(s)
Dolor/metabolismo , Canales Catiónicos TRPM/antagonistas & inhibidores , Canales Catiónicos TRPM/metabolismo , Animales , Temperatura Corporal/efectos de los fármacos , Frío , Estudios Cruzados , Método Doble Ciego , Cobayas , Células HEK293 , Humanos , Masculino , Moduladores del Transporte de Membrana/farmacología , Oxicodona/farmacología , Dolor/tratamiento farmacológico , Ratas , Ratas WistarRESUMEN
The current Covid-19 pandemic has underlined the need for a more coordinated and forward-looking investment in the search for new medicines targeting emerging health care threats. Repositioning currently approved drugs is a popular approach to any new emerging disease, but it represents a first wave of response. Behind this would be a second wave of more specifically designed therapies based on activities against specific molecular targets or in phenotypic assays. Following the successful deployment and uptake of previous open access compound collections, we assembled the Pandemic Response Box, a collection of 400 compounds to facilitate drug discovery in emerging infectious disease. These are based on public domain information on chemotypes currently in discovery and early development which have been shown to have useful activities and were prioritized by medicinal chemistry experts. They are freely available to the community as a pharmacological test set with the understanding that data will be shared rapidly in the public domain.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Pandemias , Brotes de Enfermedades , Descubrimiento de Drogas , HumanosRESUMEN
In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.
Asunto(s)
Corticoesteroides/síntesis química , Corticoesteroides/farmacocinética , Antiasmáticos/síntesis química , Antiasmáticos/farmacocinética , Asma/tratamiento farmacológico , Diseño de Fármacos , Administración por Inhalación , Corticoesteroides/administración & dosificación , Corticoesteroides/farmacología , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/uso terapéutico , Androstadienos/química , Androstadienos/farmacología , Animales , Antiasmáticos/administración & dosificación , Antiasmáticos/farmacología , Asma/epidemiología , Asma/fisiopatología , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Inhaladores de Polvo Seco , Fluticasona , Hepatocitos , Humanos , Hígado , Pulmón , Microsomas Hepáticos , Neutrófilos/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Ratas , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its receptors are heteromers comprising two distinct components: the calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of three accessory proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM1) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM2) receptor. The CTR/RAMP complexes form three distinct amylin receptors. While the selective blockade of AM2 receptors would be therapeutically valuable, inhibition of AM1 receptors would cause clinically unacceptable increased blood pressure. We report here a systematic study of structure-activity relationships that has led to the development of first-in-class AM2 receptor antagonists. These compounds exhibit therapeutically valuable properties with 1000-fold selectivity over the AM1 receptor. These results highlight the therapeutic potential of AM2 antagonists.
Asunto(s)
Receptores de Adrenomedulina/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Descubrimiento de Drogas , Femenino , Humanos , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Receptores de Adrenomedulina/metabolismo , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL.
Asunto(s)
Antiprotozoarios/uso terapéutico , Benzoxazoles/uso terapéutico , Compuestos de Boro/uso terapéutico , Leishmaniasis Visceral/tratamiento farmacológico , Piridinas/uso terapéutico , Animales , Antiprotozoarios/química , Benzoxazoles/química , Compuestos de Boro/química , Cricetinae , Modelos Animales de Enfermedad , Perros , Humanos , Ratones , Piridinas/química , Relación Estructura-ActividadRESUMEN
The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in the regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumor progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically. However, there are two distinct receptors for adrenomedullin, each comprising the same G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR), together with a different accessory protein known as a receptor activity-modifying protein (RAMP). The CLR with RAMP2 forms an adrenomedullin-1 receptor, and the CLR with RAMP3 forms an adrenomedullin-2 receptor. Recent research suggests that a selective blockade of adrenomedullin-2 receptors would be therapeutically valuable. Here we describe the design, synthesis, and characterization of potent small-molecule adrenomedullin-2 receptor antagonists with 1000-fold selectivity over the adrenomedullin-1 receptor, although retaining activity against the CGRP receptor. These molecules have clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties, and inhibit xenograft tumor growth and extend life in a mouse model of pancreatic cancer. Taken together, our data support the promise of a new class of anticancer therapeutics as well as improved understanding of the pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers.
RESUMEN
A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.
Asunto(s)
Bencilaminas/química , Química Farmacéutica/métodos , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Conformación Molecular , Receptores de Serotonina/metabolismo , Serotonina/química , Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.
Asunto(s)
Bencilaminas/síntesis química , Bencilaminas/farmacología , Éteres Fenílicos/síntesis química , Éteres Fenílicos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Bencilaminas/química , Técnicas Químicas Combinatorias , Humanos , Estructura Molecular , Éteres Fenílicos/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
The design and profile of a series of adamantyl-containing long acting beta(2)-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/farmacología , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacología , Adamantano/farmacocinética , Administración por Inhalación , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacocinética , Animales , Cobayas , Humanos , Tráquea/efectos de los fármacosRESUMEN
A highly selective method to protect the 11 beta-OH position of steroid (1) has been developed. This is achieved via double silyl protection of the 11 beta, 17 alpha-diol, followed by selective desilylation of the 17 alpha-OH under basic conditions without the need for a fluoride source.
Asunto(s)
Esteroides/química , Esteroides/síntesis química , Relación Estructura-ActividadRESUMEN
The RCN survey findings that have prompted nursing leaders to complain about the crushing weight of administration in the NHS(see page 4 )are equally applicable to other business sectors.
RESUMEN
INTRODUCTION: Asthma is a chronic condition affecting 235 million people worldwide, with prevalence continuing to increase. A significant number of patients have poorly controlled asthma but despite this, a new mechanistic class of small-molecule asthma therapy has not emerged over the past 15 years. AREAS COVERED: In this article, the authors review the published patent literature from 2013 to 2014 that describes the discovery of novel small-molecule anti-inflammatory agents for the treatment of asthma. This patent analysis was performed using multiple search engines including SciFinder and Free Patents Online. EXPERT OPINION: This review highlights that significant research is still directed towards the development of novel anti-inflammatory agents for the treatment of asthma. Current standard-of-care therapies are given topically to the lung via an inhaled dose, which the authors believe can offer significant advantages in terms of efficacy and therapeutic index, compared with an oral dose. Several of the patents reviewed disclose preferred compounds and data that suggest an inhaled approach is being specifically pursued. The patents reviewed target a wide range of inflammatory pathways, although none have yet delivered an approved novel medicine for asthma; this gives an indication of both the opportunity and challenge involved in such an endeavor.
Asunto(s)
Antiasmáticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Administración por Inhalación , Animales , Antiasmáticos/administración & dosificación , Antiinflamatorios/administración & dosificación , Diseño de Fármacos , Humanos , Patentes como AsuntoRESUMEN
Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series.
Asunto(s)
Antiparasitarios/química , Leishmania donovani/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Pirazoles/química , Urea/análogos & derivados , Urea/química , Animales , Antiparasitarios/farmacocinética , Antiparasitarios/farmacología , Cricetinae , Femenino , Humanos , Leishmaniasis Visceral/tratamiento farmacológico , Mesocricetus , Microsomas/metabolismo , Pirazoles/farmacocinética , Pirazoles/farmacología , Relación Estructura-Actividad , Urea/farmacocinética , Urea/farmacologíaRESUMEN
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
Spleen tyrosine kinase is a non-receptor tyrosine kinase, overactivation of which is thought to contribute to autoimmune diseases as well as allergy and asthma. Protein kinases have a highly conserved ATP binding site, thus making challenging the design of selective small molecule inhibitors. It has been well documented that some protein kinases can be stabilized in their inactive conformations (Type-II inhibitors). Herein, we describe a protein structure/ligand-based approach to successfully identify ligands that bind to novel conformations of spleen tyrosine kinase. By utilizing kinase protein crystal structures both in the public domain (RCSB) and within Pfizer's protein crystal database, we report the discovery of the first spleen tyrosine kinase Type-II ligands. Compounds 1 and 3 were found to bind to the DFG-out conformation of spleen tyrosine kinase, while compound 2 binds to a DFG-in, C-Helix-out conformation. In this instance, the C-helix moved significantly to create a large hydrophobic pocket rarely seen in kinase protein crystal structures.
Asunto(s)
Diseño de Fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Cristalografía por Rayos X , Bases de Datos de Proteínas , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ligandos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Proteínas Tirosina Quinasas/metabolismo , Bazo/enzimología , Quinasa SykRESUMEN
Following interrogation of a wide-ligand profile database, a nonselective norepinephrin reuptake inhibitor was converted into a novel muscarinic antagonist using two medicinal chemistry transformations (M3/NRI selectivity of >1000). Conjugation to a ß(2) agonist motif furnished a molecule with balanced dual pharmacology, as demonstrated in a guinea pig trachea tissue model of bronchoconstriction. This approach provides new starting points for the treatment of chronic obstructive pulmonary disease and illustrates the potential for building selectivity into GPCR modulators that possess intrinsic promiscuity or reverse selectivity.