RESUMEN
NaV1.7 is an actively pursued, genetically validated, target for pain. Recently reported quinolinone sulfonamide inhibitors displayed promising selectivity profiles as well as efficacy in preclinical pain models; however, concerns about off-target liabilities associated with this series resulted in an effort to reduce the lipophilicity of these compounds. Successful prosecution of this strategy was challenging due to the opposing requirement for lipophilic inhibitors for NaV1.7 potency and in vivo clearance (CL). Deconstruction of the heterocyclic core of the quinolinone series and utilization of an intramolecular hydrogen bond to mimic the requisite pharmacophore enabled the introduction of polarity without adversely impacting CL. Ultimately, this strategy led to the identification of compound 29, which demonstrated favorable ADME and was efficacious in pre-clinical models of pain.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7 , Quinolonas , Humanos , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Dolor/tratamiento farmacológico , Relación Estructura-Actividad , Sulfanilamida , Sulfonamidas/química , Sulfonamidas/farmacología , Urea/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/químicaRESUMEN
An enantioselective synthesis of (-)-10-hydroxyacutuminine is reported. Central to our strategy is a photochemical [2+2] cycloaddition that forges two of the quaternary stereocenters present in the acutumine alkaloids. A subsequent retro-aldol/Dieckmann sequence furnishes the spirocyclic cyclopentenone. Efforts to chlorinate the acutumine scaffold at C10 under heterolytic or radical deoxychlorination conditions led to the synthesis of an unexpected cyclopropane-containing pentacycle.
Asunto(s)
Ciclización , Reacción de Cicloadición , EstereoisomerismoRESUMEN
Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [ Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation . WO 2014201206, 2014 ] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Quinolonas/química , Sulfonamidas/química , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Capsaicina , Línea Celular , Perros , Histamina , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Dolor/inducido químicamente , Dolor/prevención & control , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Prurito/inducido químicamente , Prurito/prevención & control , Quinolonas/administración & dosificación , Quinolonas/síntesis química , Quinolonas/farmacocinética , Quinolonas/farmacología , Ratas , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinética , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacologíaRESUMEN
Poylcyclic tetrahydroxanthones comprise a large class of cytototoxic natural products. No mechanism of action has been described for any member of the family. We report the synthesis of kibdelone C and several simplified analogs. Both enantiomers of kibdeleone C show low nanomolar cytotoxicity toward multiple human cancer cell lines. Moreover, several simplified derivatives with improved chemical stability display higher activity than the natural product itself. In vitro studies rule out interaction with DNA or inhibition of topoisomerase, both of which are common modes of action for polycyclic aromatic compounds. However, celluar studies reveal that kibdelone C and its simplified derivatives disrupt the actin cytoseketon without directly binding actin or affecting its polymerization in vitro.
Asunto(s)
Xantonas/síntesis química , Xantonas/farmacología , Línea Celular Tumoral , Técnicas de Química Sintética , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Humanos , Xantonas/químicaAsunto(s)
Actinomycetaceae/química , Productos Biológicos/síntesis química , Isoquinolinas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antiparasitarios/síntesis química , Antiparasitarios/química , Antiparasitarios/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Línea Celular Tumoral , Humanos , Hidrogenación , Isoquinolinas/química , Isoquinolinas/farmacología , Neoplasias/tratamiento farmacológico , Estereoisomerismo , Xantonas/síntesis química , Xantonas/química , Xantonas/farmacologíaRESUMEN
The kibdelones are aromatic polyketide natural products featuring isoquinolinone and tetrahydroxanthone ring systems. They display potent cytotoxicity toward a range of human cancer cell lines. Here, we present an enantioselective total synthesis of kibdelone C that utilizes a Shi epoxidation to establish the absolute and relative stereochemistry, an acid-catalyzed cyclization to form the tetrahydroxanthone, and a C-H arylation to complete the hexacyclic skeleton.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/síntesis química , Técnicas de Química Sintética/métodos , Xantonas/química , Xantonas/síntesis química , Línea Celular Tumoral , Humanos , Estereoisomerismo , Especificidad por SustratoRESUMEN
In September 2000, the Community Members Against Discrimination (CMAD), a grassroots LGBT organization in DeKalb, Illinois, convinced their city council to add protection against discrimination on the basis of gender identity and expression. Written as an autoethnography, this essay considers the events of the campaign in terms of queer theory and the study of public argument by isolating a set of episodes that bring the reader closer to the experiences of transgender citizens who act in a public culture. The author also explores his own responsibilities as a scholar of communication, an activist, and a member of the LGBT community.
Asunto(s)
Homosexualidad , Prejuicio , Transexualidad , Femenino , Humanos , Illinois , Masculino , Política , Teoría PsicológicaRESUMEN
A combined molecular dynamics simulation and multiple ligand docking approach is applied to study the roles of the anionic subsite residues (W86, E202, Y337) in the binding of acetylcholine (ACh) to acetylcholinesterase (AChE). We find that E202 stabilizes docking of ACh via electrostatic interactions. However, we find no significant electrostatic contribution from the aromatic residues. Docking energies of ACh to mutant AChE show a more pronounced effect because of size/shape complementarity. Mutating to smaller residues results in poorer binding, both in terms of docking energy and statistical docking probability. Besides separating out electrostatics by turning off the partial charges from each residue and comparing it with the native, the mutations in this study are W86F, W86A, E202D, E202Q, E202A, Y337F, and Y337A. We also find that all perturbations result in a significant reduction in binding of extended ACh in the catalytically productive orientation. This effect is primarily caused by a small shift in preferred position of the quaternary tail.