RESUMEN
During the course of our studies on a novel HER2/EGFR dual inhibitor (TAK-285), we found an alternative potent pyrrolo[3,2-d]pyrimidine compound (1a). To enhance the pharmacokinetic (PK) profile of this compound, we conducted chemical modifications into its N-5 side chain and conversion of the chemically modified compounds into their salts. Among them, 2cb, the tosylate salt of compound 2c, showed potent HER2/EGFR kinase inhibitory activity (IC(50): 11/11 nM) and cellular growth inhibitory activity (BT-474 cell GI(50): 56 nM) with a good drug metabolism and PK (DMPK) profile. Furthermore, 2cb exhibited significant in vivo antitumor efficacy in both mouse and rat xenograft models with transplanted 4-1ST gastric cancer cell lines (mouse, T/C=0%, 2cb po bid at 100 mg/kg; rat, T/C: -1%, 2cb po bid at 25 mg/kg).
Asunto(s)
Antineoplásicos/síntesis química , Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/química , Pirimidinas/síntesis química , Pirroles/química , Receptor ErbB-2/antagonistas & inhibidores , Sulfonas/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Receptores ErbB/metabolismo , Semivida , Humanos , Ratones , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Pirroles/farmacocinética , Pirroles/uso terapéutico , Ratas , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Sulfonas/química , Sulfonas/farmacocinética , Trasplante HeterólogoRESUMEN
Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Receptores ErbB/antagonistas & inhibidores , Hidroxibutiratos/síntesis química , Pirimidinas/síntesis química , Pirroles/síntesis química , Receptor ErbB-2/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Sitios de Unión , Disponibilidad Biológica , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Hidroxibutiratos/farmacocinética , Hidroxibutiratos/farmacología , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Trasplante de Neoplasias , Conformación Proteica , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
We synthesized a series of pyrrolo[3,2-d]pyrimidine derivatives and evaluated their application as type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase. Incorporation of a diphenylurea moiety at the C4-position of the pyrrolo[3,2-d]pyrimidine core via an oxygen linker resulted in compounds that were potent inhibitors of VEGFR2 kinase. Of these derivatives, compound 20d showed the strongest inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC). The co-crystal structure of 20d and VEGFR2 revealed that 20d binds to the inactive form of VEGFR2. Further studies indicated that 20d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited PDGFR and Tie-2 kinases. Oral administration of the hydrochloride salt of 20d at 3mg/kg/day showed potent inhibition of tumor growth in a DU145 human prostate cancer cell xenograft nude mouse model.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos de Fenilurea/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/química , Pirroles/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/toxicidad , Sitios de Unión , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células Cultivadas , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Ratones , Ratones Desnudos , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/toxicidad , Estructura Terciaria de Proteína , Pirimidinas/síntesis química , Pirimidinas/toxicidad , Pirroles/síntesis química , Pirroles/toxicidad , Receptor TIE-2/antagonistas & inhibidores , Receptor TIE-2/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We have recently reported the discovery of pyrrolo[3,2-d]pyrimidine derivatives 1a and 1b as potent triple inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and Tie-2 kinases. To identify compounds having strong inhibitory activity against fibroblast growth factor receptor (FGFR) kinase, further modification was conducted using the co-crystal structure analysis of VEGFR2 and 1b. Among the compounds synthesized, urea derivative 11l having a piperazine moiety on the terminal benzene ring showed strong inhibitory activity against FGFR1 kinase as well as VEGFR2 kinase. A binding model of 11l complexed with VEGFR2 suggested that the piperazine moiety forms additional interactions with Ile1025 and His1026.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos de Fenilurea/química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Pirroles/química , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Urea/análogos & derivados , Sitios de Unión , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células Cultivadas , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptor TIE-2/antagonistas & inhibidores , Receptor TIE-2/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacologíaRESUMEN
The novel natural antibiotics pyloricidin A, B and C, consisting of a common (2S,3R,4R,5S)-5-amino-2,3,4,6-tetrahydroxyhexanoyl-beta-D-phenylalanine moiety and a terminal peptidic moiety (pyloricidin A: L-valine-L-valine-L-leucine; pyloricidin B: L-valine-L-leucine; pyloricidin C: L-leucine), exhibit potent and highly selective anti-Helicobacter pylori activity. In order to develop more potent compounds and to investigate structure activity relationships for the peptidic moiety with regard to the combination of amino acids, a series of derivatives with various dipeptidic moieties were prepared and evaluated for their anti-H. pylori activity. The combination of the two amino acids in the moiety was found to have a significant effect on the activity; the compound with Nva-Abu showed excellent anti-H. pylori activity with an MIC value of 0.013 microg/ml against H. pylori TN2. In addition, this compound was found to show 60% clearance of H. pylori from infected Mongolian gerbils upon repetitive oral administration (10 mg/kg, b. i. d. for 7 days).
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Helicobacter pylori/efectos de los fármacos , Péptidos , Animales , Antibacterianos/química , Antibacterianos/uso terapéutico , Péptidos Catiónicos Antimicrobianos , Bacterias/efectos de los fármacos , Gerbillinae , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
The novel natural antibiotics pyloricidin A, B and C, which possess potent and highly selective anti-Helicobacter pylori activity, were synthesized from D-galactosamine as a chiral template for the common (2S,3R,4R,5S)-5-amino-2,3,4,6-tetrahydroxyhexanoic acid moiety. The synthetic strategy, using 2-amino-2-deoxyuronic acid derivatives as key intermediates, was also useful to prepare a series of derivatives modified at the beta-D-phenylalanine and with altered stereochemistry on the 5-amino-2,3,4,6-tetrahydroxyhexanoic acid moiety. From the drastic decrease of their anti-H. pylori activity, it was clear that the beta-D-phenylalanine part and the stereochemistry of the 5-amino-2,3,4,6-tetrahydroxyhexanoic acid moiety were significant for the activity.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Helicobacter pylori/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
The novel natural antibiotics pyloricidin A, B and C possess potent and highly selective antibacterial activity against Helicobacter pylori. In order to investigate the structure activity relationships for the terminal peptidic moiety, a series of pyloricidin B and pyloricidin C derivatives, bearing various amino acids in the moiety, were prepared and evaluated for their anti-H. pylori activity. The derivatives bearing alpha-D-, beta- and gamma-amino acids or peptidemimetics showed drastically decreased activity. On the other hand, the derivatives with a-L-amino acids were found to maintain the activity. Among the derivatives prepared in this work, the allylglycine derivative 2s showed the most potent anti-H. pylori activity, with an MIC value of less than 0.006 microg/ml against H. pylori NCTC11637, which is 60-fold greater than the activity of the lead compound pyloricidin C.