ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Sulfoxides/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Chemical Phenomena , Clinical Trials as Topic , Female , Humans , Indoles , Mice , Models, Molecular , Molecular Conformation , Morpholines , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Sulfonamides , Sulfoxides/chemistry , Sulfoxides/pharmacokinetics , Tissue DistributionABSTRACT
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.
Subject(s)
Acculturation , Caregivers/education , Health Behavior/ethnology , Hispanic or Latino/psychology , Physician-Patient Relations , Adolescent , Adult , Caregivers/psychology , Child , Child, Preschool , Communication , Cross-Sectional Studies , Feeding Behavior , Female , Health Promotion , Hispanic or Latino/statistics & numerical data , Humans , Insurance, Health/statistics & numerical data , Male , Obesity/prevention & control , Young AdultABSTRACT
Directed screening has identified a novel series of MMP13 inhibitors that possess good levels of activity whilst possessing excellent selectivity over related MMPs. The binding mode of the series has been solved by co-crystallisation and demonstrates an interesting mode of inhibition without interaction with the catalytic zinc atom.
Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Zinc/chemistry , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Matrix Metalloproteinase 13/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel approach to inhibition of the alphavbeta3 integrin is described, which uses compounds designed to generate nM potency without using the arginine binding site.
