RESUMEN
Doxorubicin is a highly effective chemotherapy agent used to treat many common malignancies. However, its use is limited by cardiotoxicity, and cumulative doses exponentially increase the risk of heart failure. To identify novel heart failure treatment targets, a zebrafish model of doxorubicin-induced cardiomyopathy was previously established for small-molecule screening. Using this model, several small molecules that prevent doxorubicin-induced cardiotoxicity both in zebrafish and in mouse models have previously been identified. In this study, exploration of doxorubicin cardiotoxicity is expanded by screening 2271 small molecules from a proprietary, target-annotated tool compound collection. It is found that 120 small molecules can prevent doxorubicin-induced cardiotoxicity, including 7 highly effective compounds. Of these, all seven exhibited inhibitory activity towards cytochrome P450 familyâ 1 (CYP1). These results are consistent with previous findings, in which visnagin, a CYP1 inhibitor, also prevents doxorubicin-induced cardiotoxicity. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin-induced cardiotoxicity phenotypes. Together, these results provide strong evidence that CYP1 is an important contributor to doxorubicin-induced cardiotoxicity and highlight the CYP1 pathway as a candidate therapeutic target for clinical cardioprotection.
Asunto(s)
Cardiomiopatías/prevención & control , Familia 1 del Citocromo P450/metabolismo , Proteínas de Pez Cebra/metabolismo , Animales , Animales Modificados Genéticamente , Cardiomiopatías/inducido químicamente , Cardiomiopatías/patología , Familia 1 del Citocromo P450/antagonistas & inhibidores , Familia 1 del Citocromo P450/genética , Modelos Animales de Enfermedad , Doxorrubicina/toxicidad , Insuficiencia Cardíaca , Mutagénesis , Fenotipo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Pez Cebra , Proteínas de Pez Cebra/antagonistas & inhibidores , Proteínas de Pez Cebra/genéticaRESUMEN
The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current ß-lactam antibiotics and created an urgent need for novel treatment options. Using an S. aureus phenotypic screening strategy, we have identified small molecule early stage wall teichoic acid (WTA) pathway-specific inhibitors predicted to be chemically synergistic with ß-lactams. These previously disclosed inhibitors, termed tarocins, demonstrate by genetic and biochemical means inhibition of TarO, the first step in WTA biosynthesis. Tarocins demonstrate potent bactericidal synergy in combination with broad spectrum ß-lactam antibiotics across diverse clinical isolates of methicillin-resistant Staphylococci. The synthesis and structure-activity relationships (SAR) of a tarocin series will be detailed. Tarocins and other WTA inhibitors may provide a rational strategy to develop Gram-positive bactericidal ß-lactam combination agents active against methicillin-resistant Staphylococci.
Asunto(s)
Antibacterianos/química , Ácidos Teicoicos/metabolismo , beta-Lactamas/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/farmacología , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Evaluación Preclínica de Medicamentos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , beta-Lactamas/metabolismoRESUMEN
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Iminas/farmacología , Pirimidinonas/farmacología , Renina/antagonistas & inhibidores , Administración Oral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Iminas/síntesis química , Iminas/química , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aß40 levels upon subcutaneous and oral administration to rats.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Ácido Aspártico Endopeptidasas/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Diseño de Fármacos , Descubrimiento de Drogas , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Iminas/química , Iminas/uso terapéutico , Fragmentos de Péptidos/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Humanos , Iminas/farmacocinética , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/antagonistas & inhibidores , Ratas , Relación Estructura-ActividadRESUMEN
Herein, we disclose three structurally differentiated γ-secretase modulators (GSMs) based on an oxadiazine scaffold. The analogues from series I potently inhibit the generation of Aß42 in vitro when the substituents at 3 and 4 positions of the oxadiazine moiety adopt an α orientation (cf. 11). To address the concern around potential reactivity of the exocyclic double bond present in series I toward nucleophilic attack, compounds containing either an endocyclic double bond, such as 20 (series II), or devoid of an olefinic moiety, such as 27 (series III), were designed and validated as novel GSMs. Compound 11 and azepine 20 exhibit robust lowering of CSF Aß42 in rats treated with a 30 mg/kg oral dose.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Alquenos/química , Alquenos/farmacología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/líquido cefalorraquídeo , Animales , Sitios de Unión/fisiología , Células HEK293 , Humanos , Oxadiazoles/química , Oxadiazoles/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/líquido cefalorraquídeo , Ratas , Relación Estructura-ActividadRESUMEN
Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.
Asunto(s)
Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Proproteína Convertasa 9/metabolismo , Proteolisis/efectos de los fármacos , Inhibidores de Serina Proteinasa/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R=H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure-activity relationship (SAR) of these and related compounds are discussed.
Asunto(s)
Piperidinas/síntesis química , Piperidinas/farmacología , Receptores Opioides/efectos de los fármacos , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Sitios de Unión , Capsaicina/farmacología , Técnicas Químicas Combinatorias , Tos/inducido químicamente , Modelos Animales de Enfermedad , Diseño de Fármacos , Cobayas , Estructura Molecular , Piperidinas/química , Receptores Opioides/metabolismo , Compuestos de Espiro/química , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.
Asunto(s)
Ansiolíticos/síntesis química , Antitusígenos/síntesis química , Ansiedad/tratamiento farmacológico , Tos/tratamiento farmacológico , Ligandos , Tropanos/síntesis química , Animales , Ansiolíticos/farmacología , Antitusígenos/farmacología , Capsaicina/química , Química Farmacéutica/métodos , Diseño de Fármacos , Cobayas , Humanos , Receptor X de Pregnano , Receptores Opioides/química , Receptores de Esteroides/química , Relación Estructura-Actividad , Tropanos/farmacología , Receptor de NociceptinaRESUMEN
PURPOSE OF REVIEW: We examine the present global burden of Japanese encephalitis (JE) in endemic populations, summarize published cases in travelers since 2009, examine current guidelines for vaccination for international travelers, and consider challenges in prevention of this vector-borne disease. RECENT FINDINGS: We identified 11 JE cases in travelers that were published in peer-reviewed literature since 2009. JE incidence in endemic countries appears to be declining but the number of JE cases reported to the World Health Organization (WHO) varied from estimates derived from other published reports based on serosurveys or sentinel surveillance. Current JE vaccines appear to be safe and are not associated with delayed hypersensitivity in contrast to the older mouse brain vaccine. Given differences between WHO-reported cases and local surveillance data, future research on true incidence is needed. Regular assessment will inform JE risk in travelers. National and international guidelines on JE vaccination varied; we suggest areas for improvement.
RESUMEN
Two radical-based approaches have been developed to effect the trifluoromethylation of aryl C-H bonds in native peptides either using stoichiometric oxidant or visible light photoredox catalysis. The reported methods are able to derivatize tyrosine and tryptophan sidechains under biocompatible conditions, and a number of examples are reported involving fully unprotected peptides with up to 51 amino acids. The development of this chemistry adds to the growing array of chemical methods for selectively modifying amino acid residues in the context of complex peptides. The direct incorporation of trifluoromethyl groups into biopolymers enables the study of a range of biological and biochemical systems, and preliminary results indicate this method can be extended to the incorporation of other fluoroalkyl groups for bioconjugation applications.
RESUMEN
Herein we describe structure-activity relationship (SAR) and metabolite identification (Met-ID) studies that provided insight into the origin of time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4) by compound 1. Collectively, these efforts revealed that bioactivation of the fluoropyrimidine moiety of 1 led to reactive metabolite formation via oxidative defluorination and was responsible for the observed TDI. We discovered that substitution at both the 4- and 6-positions of the 5-fluoropyrimidine of 1 was necessary to ameliorate this TDI as exemplified by compound 19.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP3A/metabolismo , Pirimidinas/química , Pirimidinas/farmacología , Animales , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Humanos , Cinética , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Distribución TisularRESUMEN
We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 of 125 nM in an enzyme assay and possessed very high lipophilicity (clogP = 7.1) with no measurable solubility in PBS buffer. Structure-activity relationship (SAR) studies resulted in a series of compounds with improved lipophilic ligand efficiency (LLE) consistent with the reduction of clogP. From these efforts, analog 9 was selected for our initial in vivo study, which in combination with subefficacious dose of imipenem (IPM) robustly lowered the bacterial burden in a neutropenic Staphylococci murine infection model. Concurrent with our in vivo optimization effort using 9, we further improved LLE as exemplified by a much more druglike analog 26.
Asunto(s)
Lípidos/química , Bibliotecas de Moléculas Pequeñas , Animales , Femenino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Solubilidad , Relación Estructura-ActividadRESUMEN
We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2â³ pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aß40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aß in nonrodent preclinical species.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Diseño de Fármacos , Compuestos Heterocíclicos/química , Iminas/química , Péptidos beta-Amiloides/líquido cefalorraquídeo , Animales , Corteza Cerebral/metabolismo , Inhibidores Enzimáticos/farmacología , Macaca fascicularis , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Aß(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Nitrilos/síntesis química , Pirimidinas/síntesis química , Pirimidinonas/síntesis química , Tiofenos/síntesis química , Administración Oral , Secretasas de la Proteína Precursora del Amiloide/química , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Corteza Cerebral/metabolismo , Cristalografía por Rayos X , Células HEK293 , Humanos , Macaca fascicularis , Modelos Moleculares , Conformación Molecular , Nitrilos/farmacocinética , Nitrilos/farmacología , Fragmentos de Péptidos/metabolismo , Permeabilidad , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Teoría Cuántica , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Termodinámica , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
A series of N-substituted analogs based upon the spiropiperidine core of 1 was synthesized and exhibited high binding affinity to the nociceptin (NOP) receptor. The selectivities against other known opioid receptors were determined.
Asunto(s)
Piperidinas/síntesis química , Receptores Opioides/agonistas , Administración Oral , Animales , Tos/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Guanosina 5'-O-(3-Tiotrifosfato) , Ligandos , Farmacocinética , Piperidinas/farmacocinética , Piperidinas/farmacología , Unión Proteica , Ratas , Receptores Opioides/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
A novel series of 3-substituted-8-aryl-[1,2,4]-triazolo[5,1-i]purin-5-amine analogs related to Sch 58261 was synthesized in order to identify potent adenosine A(2A) receptor antagonists with improved selectivity over the A(1) receptor, physiochemical properties, and pharmacokinetic profiles as compared to those of Sch 58261. As a result of structural modifications, numerous analogs with excellent in vitro binding affinities and selectivities were identified. Moreover, compound 27 displayed both superior in vitro and highly promising in vivo profiles.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Fármacos Neuroprotectores/farmacología , Purinas/síntesis química , Purinas/farmacología , Pirimidinas/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Antagonistas del Receptor de Adenosina A1 , Fenómenos Químicos , Química Física , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Relación Estructura-ActividadRESUMEN
The structure-activity relationship of this novel class of compounds based on 2-(2-furanyl)-7-phenyl[1,2,4]-triazolo[1,5-c]pyrimidin-5-amine, 1, and its analogs was evaluated for their in vitro and in vivo adenosine A(2A) receptor antagonism. Several compounds displayed oral activity at 3 mg/kg in a rat catalepsy model. Specifically, compound 8g displayed an excellent in vitro profile, as well as a highly promising in vivo profile.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Pirimidinas/farmacología , Triazoles/farmacología , Administración Oral , Animales , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Masculino , Estructura Molecular , Pirimidinas/química , Pirimidinas/clasificación , Pirimidinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Triazoles/química , Triazoles/uso terapéuticoRESUMEN
The structure-activity relationship (SAR) exploration using 2-(2-furanyl)-7-phenyl[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (1) as a template led to the identification of a novel class of potent and selective adenosine A2A receptor (AR) antagonists. However, these compounds were found to be associated with significant hERG activity. This report discusses the strategy and outcome of an expanded SAR focused on addressing the hERG liability. As a result, compounds 21 and 24 possess excellent in vitro profiles, highly promising in vivo profiles, and acceptable levels of hERG channel inhibition.