RESUMEN
The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
Asunto(s)
Bencimidazoles/farmacología , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/farmacocinética , Diseño de Fármacos , Células HEK293 , Humanos , Estructura Molecular , Solubilidad , Relación Estructura-Actividad , 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
Optimization of ligand binding affinity to the target protein of interest is a primary objective in small-molecule drug discovery. Until now, the prediction of binding affinities by computational methods has not been widely applied in the drug discovery process, mainly because of its lack of accuracy and reproducibility as well as the long turnaround times required to obtain results. Herein we report on a collaborative study that compares tropomyosin receptor kinase A (TrkA) binding affinity predictions using two recently formulated fast computational approaches, namely, Enhanced Sampling of Molecular dynamics with Approximation of Continuum Solvent (ESMACS) and Thermodynamic Integration with Enhanced Sampling (TIES), to experimentally derived TrkA binding affinities for a set of Pfizer pan-Trk compounds. ESMACS gives precise and reproducible results and is applicable to highly diverse sets of compounds. It also provides detailed chemical insight into the nature of ligand-protein binding. TIES can predict and thus optimize more subtle changes in binding affinities between compounds of similar structure. Individual binding affinities were calculated in a few hours, exhibiting good correlations with the experimental data of 0.79 and 0.88 from the ESMACS and TIES approaches, respectively. The speed, level of accuracy, and precision of the calculations are such that the affinity predictions can be used to rapidly explain the effects of compound modifications on TrkA binding affinity. The methods could therefore be used as tools to guide lead optimization efforts across multiple prospective structurally enabled programs in the drug discovery setting for a wide range of compounds and targets.
Asunto(s)
Diseño de Fármacos , Dolor/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/antagonistas & inhibidores , Receptor trkA/metabolismo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Dolor/enzimología , Unión Proteica , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor trkA/química , TermodinámicaRESUMEN
The past century has witnessed an exponential increase in our atomic-level understanding of molecular and cellular mechanisms from a structural perspective, with multiple landmark achievements contributing to the field. This, coupled with recent and continuing breakthroughs in artificial intelligence methods such as AlphaFold2, and enhanced computational power, is enabling our understanding of protein structure and function at unprecedented levels of accuracy and predictivity. Here, we describe some of the major recent advances across these fields, and describe, as these technologies coalesce, the potential to utilise our enhanced knowledge of intricate cellular and molecular systems to discover novel therapeutics to alleviate human suffering.
Asunto(s)
Inteligencia Artificial , Biología , HumanosRESUMEN
The design and synthesis of a novel series of non-steroidal progesterone receptor antagonists is described. Ligand-lipophilicity efficiency (LLE) was used in the selection of a prototype agent for in vivo pharmacology studies.
Asunto(s)
Progesterona/antagonistas & inhibidores , Pirazoles/farmacología , Diseño de Fármacos , Ligandos , Modelos Moleculares , Pirazoles/farmacocinéticaRESUMEN
Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.
Asunto(s)
Descubrimiento de Drogas , Dolor/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/uso terapéutico , Ratas , Proteínas Tirosina Quinasas Receptoras/química , Proteínas Tirosina Quinasas Receptoras/metabolismo , Solubilidad , Relación Estructura-Actividad , Distribución TisularRESUMEN
Cholinergic hypofunction is associated with decreased attention and cognitive deficits in the central nervous system in addition to compromised motor function. Consequently, stimulation of cholinergic neurotransmission is a rational therapeutic approach for the potential treatment of a variety of neurological conditions. High affinity choline uptake (HACU) into acetylcholine (ACh)-synthesizing neurons is critically mediated by the sodium- and pH-dependent high-affinity choline transporter (CHT, encoded by the SLC5A7 gene). This transporter is comparatively well-characterized but otherwise unexplored as a potential drug target. We therefore sought to identify small molecules that would enable testing of the hypothesis that positive modulation of CHT mediated transport would enhance activity-dependent cholinergic signaling. We utilized existing and novel screening techniques for their ability to reveal both positive and negative modulation of CHT using literature tools. A screening campaign was initiated with a bespoke compound library comprising both the Pfizer Chemogenomic Library (CGL) of 2,753 molecules designed specifically to help enable the elucidation of new mechanisms in phenotypic screens and 887 compounds from a virtual screening campaign to select molecules with field-based similarities to reported negative and positive allosteric modulators. We identified a number of previously unknown active and structurally distinct molecules that could be used as tools to further explore CHT biology or as a starting point for further medicinal chemistry.
RESUMEN
The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.
Asunto(s)
Descubrimiento de Drogas , Dolor/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirimidinas/farmacología , Pirroles/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Dolor/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad CuantitativaRESUMEN
Pain is a complex disease which can progress into a debilitating condition. The effective treatment of pain remains a challenge as current therapies often lack the desired level of efficacy or tolerability. One therapeutic avenue, the modulation of ion channel signaling by small molecules, has shown the ability to treat pain. However, of the 215 ion channels that exist in the human genome, with 85 ion channels having a strong literature link to pain, only a small number of these channels have been successfully drugged for pain. The focus of future research will be to fully explore the possibilities surrounding these unexplored ion channels. Toward this end, a greater understanding of ion channel modulation will be the greatest tool we have in developing the next generation of drugs for the treatment of pain.
Asunto(s)
Anestésicos/farmacología , Dolor/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio Activados por Voltaje/metabolismo , Anestésicos/uso terapéutico , Animales , Humanos , Nocicepción/efectos de los fármacos , Bloqueadores de los Canales de Sodio/uso terapéuticoRESUMEN
Ion channels are membrane proteins expressed in almost all living cells. The sequencing of the human genome has identified more than 400 putative ion channels, but only a fraction of these have been cloned and functionally tested. The widespread tissue distribution of ion channels, coupled with the plethora of physiological consequences of their opening and closing, makes ion-channel-targeted drug discovery highly compelling. However, despite some important drugs in clinical use today, as a class, ion channels remain underexploited in drug discovery and many existing drugs are poorly selective with significant toxicities or suboptimal efficacy. This Perspective seeks to review the ion channel family, its structural and functional features, and the diseases that are known to be modulated by members of the family. In particular, we will explore the structure and properties of known ligands and consider the future prospects for drug discovery in this challenging but high potential area.
Asunto(s)
Descubrimiento de Drogas , Canales Iónicos/efectos de los fármacos , Humanos , Canales Iónicos/química , Modelos Moleculares , FilogeniaRESUMEN
An efficient synthesis of NP25302 is presented that relies on 5-endo-dig N-cyclization to establish the bicyclic core and Curtius rearrangement to install the N-acyl vinylogous urea functionality.