RESUMEN
We theoretically show that the coupling between magnons in an antiferromagnetically coupled ferrimagnet and microwave photons in a cavity is largely enhanced at the angular momentum compensation point (T_{A}) when T_{A} is distinct from the magnetization compensation point. The origin of the enhanced magnon-photon coupling at T_{A} is identified as the antiferromagnetic spin dynamics combined with a finite magnetization. Moreover, we show that strong magnon-photon coupling can be achieved at high excitation frequency in a ferrimagnet, which is challenging to achieve for a ferromagnet due to low magnon frequency and for an antiferromagnet due to weak magnon-photon coupling. Our results will invigorate research on magnon-photon coupling by proposing ferrimagnets as a versatile platform that offers advantages of both ferromagnets and antiferromagnets.
RESUMEN
IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis. Herein we report the identification and optimization of a series of potent IRAK4 inhibitors. Representative examples from this series showed excellent selectivity over a panel of kinases, including the kinases known to play a role in TLR-mediated signaling. The compounds exhibited low nM potency in LPS- and R848-induced cytokine assays indicating that they are blocking the TLR signaling pathway. A key compound (26) from this series was profiled in more detail and found to have an excellent pharmaceutical profile as measured by predictive assays such as microsomal stability, TPSA, solubility, and clogP. However, this compound was found to afford poor exposure in mouse upon IP or IV administration. We found that removal of the ionizable solubilizing group (32) led to increased exposure, presumably due to increased permeability. Compounds 26 and 32, when dosed to plasma levels corresponding to ex vivo whole blood potency, were shown to inhibit LPS-induced TNFα in an in vivo murine model. To our knowledge, this is the first published in vivo demonstration that inhibition of the IRAK4 pathway by a small molecule can recapitulate the phenotype of IRAK4 knockout mice.
Asunto(s)
Indoles/química , Indoles/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Femenino , Humanos , Indoles/farmacocinética , Quinasas Asociadas a Receptores de Interleucina-1/inmunología , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/farmacocinética , Transducción de Señal/efectos de los fármacosRESUMEN
The pyranonaphthoquinones (+)-7-deoxyfrenolicin B and (+)-7-deoxykalafungin were synthesized in four steps using an oxa-Pictet-Spengler cyclization that directly provided the natural (3a,5)-trans-substituted dihydronaphthopyrans with high diastereoselectivity. This outcome is in contrast to the unnatural (3a,5)-cis-substituted dihydronaphthopyrans reported under similar conditions for the syntheses of (+)-frenolicin B and (+)-kalafungin. Computational modeling is presented that provides insight into this unusual stereoselectivity.
Asunto(s)
Naftoquinonas/síntesis química , Ciclización , Conformación Molecular , Naftoquinonas/química , EstereoisomerismoRESUMEN
A series of 5-vinyl phenyl sulfonamide-3-pyridinecarbonitriles were prepared and evaluated as PKCtheta inhibitors. Optimization resulted in the identification of compound 15 with an IC(50) value 0.44 nM for the inhibition of PKCtheta with 150-fold selectivity over PKCdelta.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Piridinas/síntesis química , Piridinas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Diseño de Fármacos , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/química , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A series of 5-vinyl-3-pyridinecarbonitriles were synthesized and evaluated as PKCtheta inhibitors. The systematic optimization of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-3-pyridinecarbonitrile 3 resulted in the identification of compound 23e as a potent PKCtheta inhibitor with good selectivity over PKCdelta.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Nitrilos/química , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Animales , Humanos , Isoenzimas/metabolismo , Microsomas/metabolismo , Nitrilos/síntesis química , Nitrilos/farmacología , Proteína Quinasa C/metabolismo , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C-theta , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis and optimization of a class of trisubstituted quinazoline-2,4(1H,3H)-dione cPLA(2)alpha inhibitors are described. Utilizing pharmacophores that were found to be important in our indole series, we discovered inhibitors with reduced lipophilicity and improved aqueous solubility. These compounds are active in whole blood assays, and cell-based assay results indicate that prevention of arachidonic acid release arises from selective cPLA(2)alpha inhibition.
Asunto(s)
Compuestos de Bencidrilo/síntesis química , Compuestos de Bencidrilo/farmacología , Fosfolipasas A2 Grupo IV/antagonistas & inhibidores , Fosfolipasas A2 Grupo IV/metabolismo , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Animales , Ácido Araquidónico/metabolismo , Compuestos de Bencidrilo/química , Sangre/efectos de los fármacos , Sangre/metabolismo , Línea Celular , Humanos , Quinazolinonas/química , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A2alpha (cPLA2alpha, type IVA phospholipase) are described. Inhibitors of cPLA2alpha are predicted to be efficacious in treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. The introduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of these inhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a sub-micromolar inhibitor of cPLA2alpha in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Benzoatos/síntesis química , Citosol/enzimología , Indoles/síntesis química , Fosfolipasas A/antagonistas & inhibidores , Sulfonamidas/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Benzoatos/farmacocinética , Benzoatos/farmacología , Carragenina , Edema/inducido químicamente , Edema/tratamiento farmacológico , Fosfolipasas A2 Grupo IV , Humanos , Técnicas In Vitro , Indoles/farmacocinética , Indoles/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.