RESUMEN
Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.
Asunto(s)
Neoplasias de la Mama , Receptores de Estrógenos , Ratones , Humanos , Animales , Femenino , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Antagonistas de Estrógenos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptor alfa de Estrógeno/metabolismo , Línea CelularRESUMEN
In this report, we describe a new photoredox catalyzed 1,4-conjugate addition of N-substituted acetic acids to electron-deficient olefins via decarboxylative C-C bond formation. This C-C bond formation occurred under mild conditions enabled by visible light irradiation. This transformation facilitated the synthesis of biologically relevant N-substituted heterocyclic structural motifs not readily accessible by other methods. The C-C bond formation protocol was applied to weakly nucleophilic heterocycles such as indoles, indazoles, imidazoles, and cyclic amides to form functionalized drug-like small molecule.
Asunto(s)
Alquenos , Electrones , Acetatos/química , Alquenos/química , Catálisis , Descarboxilación , Metano/análogos & derivadosRESUMEN
A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
Asunto(s)
Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Animales , Apoptosis/efectos de los fármacos , Sitios de Unión , Línea Celular Tumoral , Quinasa 9 Dependiente de la Ciclina/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Semivida , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Humanos , Ratones , Simulación del Acoplamiento Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Ratas , Solubilidad , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.
Asunto(s)
Antineoplásicos/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Administración Oral , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Ciclización , Descubrimiento de Drogas , Femenino , Humanos , Lípidos/química , Estructura Molecular , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , Relación Estructura-ActividadRESUMEN
[reaction: see text] A highly useful sequence of reactions is described here. These reactions consist of the first successful base-induced isomerizations of propargyl amides to chiral ynamides, applications of these novel ynamides in ring-closure metathesis leading to chiral 2-amidodienes useful for Diels-Alder cycloadditions, and the first successful tandem RCM of diene-ynamides.
RESUMEN
The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.
Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Haemophilus influenzae/enzimología , ARNt Metiltransferasas/antagonistas & inhibidores , Adenosina/metabolismo , Aminas/síntesis química , Aminas/química , Aminas/metabolismo , Aminas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Haemophilus influenzae/efectos de los fármacos , Humanos , Metionina/metabolismo , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Terciaria de Proteína , ARN de Transferencia/química , ARN de Transferencia/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato , ARNt Metiltransferasas/química , ARNt Metiltransferasas/metabolismoRESUMEN
Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. Aminopiperidines that have a bicyclic aromatic moiety linked through a carbon to an ethyl bridge, such as 1, generally show potent broad-spectrum antibacterial activity, including quinolone-resistant isolates, but suffer from potent hERG inhibition (IC(50)= 3 µM for 1). We now disclose the finding that new analogues of 1 with an N-linked cyclic amide moiety attached to the ethyl bridge, such as 24m, retain the broad-spectrum antibacterial activity of 1 but show significantly less hERG inhibition (IC(50)= 31 µM for 24m) and higher free fraction than 1. One optimized analogue, compound 24l, showed moderate clearance in the dog and promising efficacy against Staphylococcus aureus in a mouse thigh infection model.
Asunto(s)
Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , ADN-Topoisomerasas de Tipo II/metabolismo , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Piperidinas/síntesis química , Inhibidores de Topoisomerasa/síntesis química , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Perros , Farmacorresistencia Bacteriana , Canal de Potasio ERG1 , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacología , Conformación Proteica , Ratas , Infecciones Estafilocócicas/tratamiento farmacológico , Relación Estructura-Actividad , Inhibidores de Topoisomerasa/farmacocinética , Inhibidores de Topoisomerasa/farmacologíaRESUMEN
The first X-ray structure of an unsubstituted allenamide, C(19)H(17)NO(2), is reported. The solid-state phase supports the notion that a key minimum conformation of allenamides can be invoked to rationalize the observed stereochemical outcomes in many of our methodological studies employing allenamides. This minimum conformation involves two important factors, i.e. having approximate coplanarity between the planes of the oxazolidinone ring and the internal olefin, and having the allene moiety facing away from the carbamate carbonyl group. The C-N-C=C torsion angle that quantifies this approximate coplanarity between the plane of the oxazolidinone ring and that of the internal olefin, as determined from this crystallographic study, is -19.1 (2) degrees . A minimized structural calculation, which determined this angle to be -16.1 degrees , is in close agreement. Additional structural features include a probable pi-pi interaction between the allene moiety and a benzene ring, and non-classical hydrogen bonding in the form of weak C-H...O interactions that are responsible for the formation of two-dimensional networks.