RESUMEN
Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Cinesinas/antagonistas & inhibidores , Neoplasias/enzimología , Piperidinas/farmacología , Pirroles/farmacología , Taxoides/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Taxoides/uso terapéuticoRESUMEN
3,5-diaryl-4,5-dihydropyrazoles were discovered to be potent KSP inhibitors with excellent in vivo potency. These enzyme inhibitors possess desirable physical properties that can be readily modified by incorporation of a weakly basic amine. Careful adjustment of amine basicity was essential for preserving cellular potency in a multidrug resistant cell line while maintaining good aqueous solubility.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Antimitóticos/síntesis química , Antimitóticos/farmacología , Cinesinas/antagonistas & inhibidores , Mitosis/efectos de los fármacos , Pirazoles/síntesis química , Pirazoles/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Fenómenos Químicos , Química Física , Diseño de Fármacos , Resistencia a Antineoplásicos , Genes MDR/efectos de los fármacos , Humanos , Indicadores y Reactivos , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Inspired by previous efforts in the pyrazolobenzoxazine class of KSP inhibitors, the design and synthesis of 1,4-diaryl-4,5-dihydropyrazole inhibitors of KSP are described. Crystallographic evidence of binding mode and in vivo potency data is also highlighted.
Asunto(s)
Diseño de Fármacos , Hidrógeno/química , Cinesinas/antagonistas & inhibidores , Cinesinas/metabolismo , Mitosis/efectos de los fármacos , Pirazoles/química , Pirazoles/farmacología , Sitios de Unión , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Relación Estructura-ActividadRESUMEN
Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Flúor/metabolismo , Cinesinas/antagonistas & inhibidores , Propilaminas/farmacología , Pirroles/farmacología , Transporte Biológico , Citoesqueleto , Concentración de Iones de Hidrógeno , Cinesinas/metabolismo , Solubilidad , AguaRESUMEN
Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.
Asunto(s)
Benzoxazinas/química , Benzoxazinas/farmacología , Diseño de Fármacos , Cinesinas/antagonistas & inhibidores , Cinesinas/metabolismo , Mitosis/efectos de los fármacos , Pirazoles/química , Animales , Benzoxazinas/síntesis química , Benzoxazinas/farmacocinética , Línea Celular , Perros , Humanos , Hidrógeno/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.
Asunto(s)
Diseño de Fármacos , Cinesinas/antagonistas & inhibidores , Pirazoles/química , Pirazoles/farmacología , Alquilación , Sitio Alostérico , Aminación , Animales , Cristalografía por Rayos X , Perros , Hidroxilación , Cinesinas/química , Cinesinas/metabolismo , Mitosis , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/farmacocinética , Solubilidad , Relación Estructura-Actividad , AguaRESUMEN
2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy.