RESUMO
Thirty-six novel acylurea connected straight chain hydroxamates were designed and synthesized. Structure-activity relationships (SAR) were established for the length of linear chain linker and substitutions on the benzoylurea group. Compounds 5g, 5i, 5n, and 19 showed 10-20-fold enhanced HDAC1 potency compared to SAHA. In general, the cellular potency pIC(50) (COLO205) correlates with enzymatic potency pIC(50) (HDAC1). Compound 5b (SB207), a structurally simple and close analogue to SAHA, is more potent against HDAC1 and HDAC6 compared to the latter. As a representative example of this series, good in vitro enzymatic and cellular potency plus an excellent pharmacokinetic profile has translated into better efficacy than SAHA in both prostate cancer (PC3) and colon cancer (HCT116) xenograft models.
Assuntos
Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Ureia/farmacologia , Animais , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/química , Cinética , Camundongos , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
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.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Aurora Quinases , Avaliação Pré-Clínica de Medicamentos , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
A series of N-hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides were designed and synthesized as novel HDAC inhibitors. General SAR has been established for the substituents at positions 1 and 2, as well as the importance of the ethylene group and its attachment to position 5. Optimized compounds are much more potent than SAHA in both enzymatic and cellular assays. A representative compound, 23 (SB639), has demonstrated antitumor activity in a colon cancer xenograft model.
Assuntos
Acrilamidas/síntese química , Antineoplásicos/síntese química , Benzimidazóis/síntese química , Inibidores de Histona Desacetilases , Acrilamidas/administração & dosagem , Acrilamidas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Células HCT116 , Histona Desacetilases/metabolismo , Humanos , Camundongos , Camundongos Nus , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).
Assuntos
Indenos/síntese química , Morfolinas/síntese química , Pirimidinas/síntese química , Receptores LHRH/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Técnicas In Vitro , Indenos/química , Indenos/farmacologia , Fosfatos de Inositol/biossíntese , Masculino , Morfolinas/química , Morfolinas/farmacologia , Orquiectomia , Hipófise/metabolismo , Pirimidinas/química , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testosterona/antagonistas & inibidores , Testosterona/metabolismoRESUMO
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.
Assuntos
Antirreumáticos/síntese química , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Janus Quinase 2/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Linhagem Celular , Permeabilidade da Membrana Celular , Colágeno Tipo II , Cães , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Janus Quinase 2/fisiologia , Macaca mulatta , Masculino , Camundongos , Camundongos Nus , Microssomos/metabolismo , Modelos Moleculares , Ratos , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , TYK2 Quinase/antagonistas & inibidoresRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Janus Quinase 3/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Transplante de Neoplasias , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Janus Quinase 2/antagonistas & inibidores , Linfoma/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Pirimidinas/síntese química , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Trifosfato de Adenosina/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Sítios de Ligação , Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Técnicas In Vitro , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Transplante de Neoplasias , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Solubilidade , Transplante Heterólogo , Transplante HomólogoRESUMO
A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.