RESUMEN
Reducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded > fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.
Asunto(s)
Células Madre Pluripotentes Inducidas/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Infarto del Miocardio/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Células Madre Pluripotentes Inducidas/enzimología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Infarto del Miocardio/enzimología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Profármacos/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Sus scrofa , Investigación Biomédica Traslacional , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
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
New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
Asunto(s)
Azepinas/síntesis química , Pirimidinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Animales , Azepinas/química , Azepinas/farmacología , Azepinas/uso terapéutico , Modelos Animales de Enfermedad , Perros , Masculino , Estructura Molecular , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Agonistas del Receptor de Serotonina 5-HT2/química , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Incontinencia Urinaria/tratamiento farmacológicoRESUMEN
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
New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
Asunto(s)
Inhibidores de Captación Adrenérgica/química , Norepinefrina , Piperazinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Incontinencia Urinaria de Esfuerzo/tratamiento farmacológico , Inhibidores de Captación Adrenérgica/metabolismo , Inhibidores de Captación Adrenérgica/farmacocinética , Animales , Perros , Humanos , Piperazinas/metabolismo , Piperazinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Relación Estructura-ActividadRESUMEN
2-((R-5-chloro-4-methoxymethyl-indan-1-yl)-1H-imidazole (PF-3774076) is a central nervous system (CNS) penetrant, potent, selective, partial agonist at the human alpha1(A)-adrenoceptor, demonstrating efficacy and selectivity in a range of binding and functional assays. In vivo, PF-3774076 increases peak urethral pressure in anesthetized female dogs in a dose-dependent manner, inducing changes in both the proximal and distal portions of the urethra via a central mechanism of action. The profile of this compound suggests that a CNS penetrant partial agonist at the alpha1(A)-adrenoceptor may offer significant benefit in stress urinary incontinence (SUI). However, despite partial agonism at the alpha1(A)-adrenoceptor and selectivity over alpha1(B)- and alpha1(D)-adrenoceptors, PF-3774076 did not offer the necessary degree of separation over cardiovascular events when assessed in in vivo models of cardiovascular function. This may be due to activation of both peripheral and central alpha1(A)-adrenoceptors. These data indicate that although central, partial alpha1(A)-agonists may offer significant benefit in the treatment of SUI, it may not be possible to achieve the desired level of urethral selectivity over cardiovascular events with this class of agent.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1 , Agonistas alfa-Adrenérgicos/farmacología , Imidazoles/farmacología , Uretra/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Línea Celular , Cricetinae , Cricetulus , ADN Complementario/biosíntesis , ADN Complementario/genética , Perros , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Humanos , Ensayo de Unión Radioligante , Receptores Adrenérgicos alfa 1/biosíntesis , Sulfonamidas/farmacología , Telemetría , Uretra/metabolismoRESUMEN
Novel pyrroloimidazoles have been identified as potent partial agonists of the alpha(1A) adrenergic receptor, with good selectivity over the alpha(1B), alpha(1D) and alpha(2A) receptor subtypes. Pyrimidine 19 possessed attractive CNS drug-like properties with good membrane permeability and no evidence for P-gp mediated efflux.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1 , Imidazoles/química , Imidazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2 , Animales , Línea Celular , Perros , Humanos , Imidazoles/metabolismo , Microsomas Hepáticos/metabolismo , Pirimidinas/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismoRESUMEN
A series of 2-pyridyl pyrimidines, reported inhibitors of Plasmodium falciparum methionine aminopeptidase 1b were synthesized and evaluated for their antiplasmodial activities. An analysis of physicochemical properties demonstrated a link between lipophilicity and antiparasitic activity. Cross screening of the library against cultured Leishmania donovani parasites revealed this class of compounds as potent inhibitors of parasite development in vitro.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Evaluación Preclínica de Medicamentos , Relación Estructura-ActividadRESUMEN
A dual activity, conjugated approach has been taken to form hybrid molecules of two known antimalarial drugs, chloroquine (CQ) and the non-sedating H1 antagonist astemizole. A variety of linkers were investigated to conjugate the two agents into one molecule. Compounds 5-8 possessed improved in vitro activity against a CQ-resistant strain of Plasmodium falciparum, and examples 7 and 8 were active in vivo in mouse models of malaria.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Astemizol/química , Cloroquina/química , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/uso terapéutico , Astemizol/farmacología , Astemizol/uso terapéutico , Cloroquina/farmacología , Cloroquina/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Malaria Falciparum/tratamiento farmacológico , RatonesRESUMEN
Novel imidazole frameworks have been identified as potent partial agonists of the alpha(1A) adrenergic receptor, with good selectivity over the alpha(1B), alpha(1D) and alpha(2A) receptor sub-types. Nitrile 28 possessed attractive CNS drug-like properties with good membrane permeability and no P-pg mediated efflux. 28 also possessed excellent solubility, metabolic stability and wide ligand selectivity.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1 , Imidazoles/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2 , Animales , Línea Celular , Perros , Humanos , Imidazoles/síntesis química , Imidazoles/farmacocinética , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismoRESUMEN
A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT(2C) agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT(2C) agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT(2B). Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.
Asunto(s)
Azepinas/química , Pirimidinas/química , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/química , Incontinencia Urinaria/tratamiento farmacológico , Animales , Azepinas/síntesis química , Azepinas/farmacología , Células CHO , Línea Celular , Cricetinae , Cricetulus , Perros , Descubrimiento de Drogas , Humanos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/farmacología , TransfecciónRESUMEN
Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
Asunto(s)
Inhibidores de Captación Adrenérgica/química , Norepinefrina/metabolismo , Piperidinas/química , Pirrolidinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacocinética , Animales , Diseño de Fármacos , Piperidinas/síntesis química , Piperidinas/farmacocinética , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Inhibidores de Captación Adrenérgica/química , Anilidas/química , Benzamidas/química , Sistema Nervioso Central/metabolismo , Pirrolidinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacocinética , Anilidas/síntesis química , Anilidas/farmacología , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Línea Celular , Perros , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/farmacocinética , Humanos , Norepinefrina/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Relación Estructura-ActividadRESUMEN
A novel series of 1-(2-phenoxyphenyl)methanamines is disclosed, which possess selective dual 5-HT and NA reuptake pharmacology. Analogues with good human in vitro metabolic stability, hERG selectivity and passive membrane permeability were identified.
Asunto(s)
Aminas/química , Aminas/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Canal de Potasio ERG1 , Humanos , Técnicas In Vitro , Conformación Molecular , Relación Estructura-ActividadRESUMEN
A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P>3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.
Asunto(s)
Aminas/farmacología , Hepatocitos/efectos de los fármacos , Norepinefrina/antagonistas & inhibidores , Éteres Fenílicos/farmacología , Piridinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas del Receptor de Serotonina 5-HT1 , Aminas/síntesis química , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Éteres Fenílicos/síntesis química , Piridinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Relación Estructura-ActividadRESUMEN
Novel 2-imidazoles have been identified as potent partial agonists of the alpha(1A) adrenergic receptor, with good selectivity over the alpha(1B), alpha(1D) and alpha(2A) receptor sub-types. Sulfonamide 23 possessed attractive drug-like properties with respect to physicochemical and ADME properties and wide ligand selectivity.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1 , Agonistas alfa-Adrenérgicos/uso terapéutico , Imidazoles/uso terapéutico , Incontinencia Urinaria/tratamiento farmacológico , Agonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/síntesis química , Humanos , Imidazoles/síntesis química , Modelos Químicos , Receptores Adrenérgicos alfa 1 , Receptores Adrenérgicos alfa 2 , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identified as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming good CNS penetration.
Asunto(s)
Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Sistema Nervioso Central/efectos de los fármacos , Técnicas Químicas Combinatorias , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pirrolidinas/química , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/química , EstereoisomerismoRESUMEN
The structure-activity relationship and the synthesis of novel N-benzyl-N-(pyrrolidin-3-yl)carboxamides as dual serotonin (5-HT) and noradrenaline (NA) monoamine reuptake inhibitors are described. Compounds such as 18 exhibited dual 5-HT and NA reuptake inhibition, good selectivity over dopamine (DA) reuptake inhibition and drug-like physicochemical properties consistent with CNS target space. Compound 18 was selected for further preclinical evaluation.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Norepinefrina/análisis , Pirrolidinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Serotonina/análisis , Amidas/química , Animales , Sistema Nervioso Central/efectos de los fármacos , Técnicas Químicas Combinatorias , Inhibidores del Citocromo P-450 CYP2D6 , Perros , Inhibidores de Captación de Dopamina/farmacología , Diseño de Fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Conformación Molecular , Pirrolidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of central nervous system (CNS) penetrant indane 2-imidazoles have been identified as potent, partial agonists of the alpha(1A) adrenergic receptor, having good selectivity over the alpha(1B), alpha(1D) and alpha(2) sub-types. A key structural motif to impart selectivity is a methylene spacer between the indane and a pendant substituent, which includes heterocycles, sulphones and ethers. Introduction of an ortho-halogen to this group led to a lowering of intrinsic efficacy (E(max)).
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1 , Sistema Nervioso Central/efectos de los fármacos , Química Farmacéutica/métodos , Imidazoles/síntesis química , Imidazoles/farmacología , Secuencias de Aminoácidos , Cromatografía Líquida de Alta Presión , Diseño de Fármacos , Halógenos/química , Humanos , Cinética , Microsomas Hepáticos/efectos de los fármacos , Modelos Químicos , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.