RESUMEN
The powerful olefin metathesis reaction was employed for the construction of late-phase clinical agents SB1317 and SB1518. In both cases RCM seems to proceed only in the presence of an acid and to predominantly furnish trans isomers. In case of SB1518 it proceeded in the presence of acid HCl, while for SB1317, it mainly proceeds in the presence of TFA (trifluroacetic acid).
Asunto(s)
Antineoplásicos/síntesis química , Hidrocarburos Aromáticos con Puentes/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Antineoplásicos/farmacología , Hidrocarburos Aromáticos con Puentes/farmacología , Ensayos Clínicos como Asunto , Ciclización , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Janus Quinasa 2/química , Janus Quinasa 2/metabolismo , Linfoma/tratamiento farmacológico , Linfoma/enzimología , Estructura Molecular , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , EstereoisomerismoRESUMEN
Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity against PDK1 in a biochemical enzyme assay.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinonas/síntesis química , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Animales , Antineoplásicos/farmacología , Dominio Catalítico , Simulación por Computador , Diseño de Fármacos , Humanos , Cinética , Ligandos , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinonas/farmacologíaRESUMEN
Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.
Asunto(s)
Antirreumáticos/síntesis química , Artritis Reumatoide/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Janus Quinasa 2/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Antirreumáticos/farmacocinética , Antirreumáticos/farmacología , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Línea Celular , Permeabilidad de la Membrana Celular , Colágeno Tipo II , Perros , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Janus Quinasa 2/fisiología , Macaca mulatta , Masculino , Ratones , Ratones Desnudos , Microsomas/metabolismo , Modelos Moleculares , Ratas , Transducción de Señal/efectos de los fármacos , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , TYK2 Quinasa/antagonistas & inhibidoresRESUMEN
Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
Asunto(s)
Antineoplásicos/síntesis química , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Janus Quinasa 3/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.
Asunto(s)
Antineoplásicos/síntesis química , Hidrocarburos Aromáticos con Puentes/síntesis química , Janus Quinasa 2/antagonistas & inhibidores , Linfoma/tratamiento farmacológico , Mielofibrosis Primaria/tratamiento farmacológico , Pirimidinas/síntesis química , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Adenosina Trifosfato/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Sitios de Unión , Hidrocarburos Aromáticos con Puentes/farmacocinética , Hidrocarburos Aromáticos con Puentes/farmacología , Línea Celular Tumoral , Perros , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Técnicas In Vitro , Ratones , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Solubilidad , Trasplante Heterólogo , Trasplante HomólogoRESUMEN
A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays.