RESUMEN
A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a serine-threonine kinase thought to play a role in the PI3K/Akt signaling pathway, a key mediator of cancer cell growth, survival and tumorigenesis. The synthesis, SAR and ADME properties of this series of compounds are discussed culminating in the discovery of compound 6 which possessed sub-micromolar cell proliferation activity and 65% oral bioavailability in mice.
Asunto(s)
Compuestos de Anilina/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Purinas/química , Bibliotecas de Moléculas Pequeñas/química , Compuestos de Anilina/farmacología , Animales , Línea Celular Tumoral , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Purinas/farmacología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Bibliotecas de Moléculas Pequeñas/farmacología , SolubilidadRESUMEN
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.