RESUMO
A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing mice, 14 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed with 14 in only a small subset of the over 200 cancer cell lines examined, consistent with other published IAP inhibitors. As a result of its in vitro and in vivo profile, 14 was nominated as a candidate for clinical development.
Assuntos
Alcinos/farmacologia , Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Descoberta de Drogas , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Oligopeptídeos/farmacologia , Alcinos/síntese química , Alcinos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Conformação Molecular , Neoplasias/patologia , Oligopeptídeos/síntese química , Oligopeptídeos/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.
Assuntos
Aminoquinolinas/síntese química , Aminoquinolinas/toxicidade , Compostos de Anilina/síntese química , Compostos de Anilina/toxicidade , Sistema Cardiovascular/efeitos dos fármacos , Inibidores Enzimáticos/toxicidade , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/toxicidade , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cobaias , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , RatosRESUMO
A series of structurally unique Smac mimetics that act as antagonists of inhibitor of apoptosis proteins (IAPs) has been discovered. While most previously described Smac mimetics contain the proline ring (or a similar cyclic motif) found in Smac, a key feature of the compounds described herein is that this ring has been removed. Despite this, compounds in this series potently bind to cIAP1 and elicit the expected phenotype of cIAP1 inhibition in cancer cells. Marked selectivity for cIAP1 over XIAP is observed for these compounds, which is attributed to a slight difference in the binding groove between the two proteins and the resulting steric interactions with the inhibitors. XIAP binding can be improved by constraining the inhibitor so that these unfavorable steric interactions are minimized.
Assuntos
Aminas/síntese química , Desenho de Fármacos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteínas Mitocondriais/química , Piperidinas/síntese química , Aminas/química , Aminas/farmacologia , Proteínas Reguladoras de Apoptose , Biomimética , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.
RESUMO
3-Amido-4-anilinocinnolines have been identified as potent and highly selective inhibitors of CSF-1R. The synthesis and SAR of these compounds is reported, along with some physical property, pharmacokinetic and kinase selectivity data.
Assuntos
Amidas/síntese química , Compostos de Anilina/síntese química , Compostos Heterocíclicos com 2 Anéis/síntese química , Inibidores de Proteínas Quinases/síntese química , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Amidas/química , Compostos de Anilina/química , Animais , Cães , Compostos Heterocíclicos com 2 Anéis/química , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Ratos , Relação Estrutura-AtividadeRESUMO
The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified.
Assuntos
Química Farmacêutica/métodos , Neoplasias/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacocinética , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptor de Fator Estimulador de Colônias de Macrófagos/química , Aminas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Modelos Químicos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , RatosRESUMO
3-amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions.
Assuntos
Química Farmacêutica/métodos , Neoplasias/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacocinética , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptor de Fator Estimulador de Colônias de Macrófagos/química , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , RatosRESUMO
The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples.
Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Tiazóis/farmacologia , Células 3T3 , Amidas/química , Amidas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Feminino , Humanos , Camundongos , Camundongos Nus , Ratos , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.