RESUMO
The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.
Assuntos
Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfóxidos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Fenômenos Químicos , Ensaios Clínicos como Assunto , Feminino , Humanos , Indóis , Camundongos , Modelos Moleculares , Conformação Molecular , Morfolinas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Sulfonamidas , Sulfóxidos/química , Sulfóxidos/farmacocinética , Distribuição TecidualRESUMO
The present study was part of a larger randomized controlled childhood obesity prevention trial based in 11 public recreation centers. The primary aim was to evaluate the effectiveness of a multi-level intervention to prevent the onset of overweight and obesity among children (5-8 years of age). However, the purpose of the current study was to identify sociodemographic variables, such as acculturation, that were associated with receipt of physician advice among Latino primary caregivers. Participants included 221 Latino primary caregivers and their children from San Diego, CA. Cross-sectional baseline data suggested that Latino children with private insurance were more likely to receive physician advice regarding their eating habits. Conversely, primary caregivers between the ages of 30-39 were less likely to receive physician advice regarding their child's eating habits. Current findings highlight the continued need to improve preventive efforts and reduce health disparities among a vulnerable population, such as Latinos.