ABSTRACT
A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development.
Subject(s)
Amides/chemistry , Renin/antagonists & inhibitors , Administration, Oral , Amides/pharmacokinetics , Amides/pharmacology , Animals , Biological Availability , Humans , Macaca fascicularis , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Renin/blood , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
Renin inhibitors containing a 4,5- or a 3,5-dihydroxy-2-substituted-6-phenylhexanamide fragment at the P2-P3 sites have been prepared and evaluated. The four possible diastereomeric diols of the two series of inhibitors were synthesized to determine the optimal configuration of the carbinol centers for these replacements. The most potent inhibitors of each series, la and 2c have a molecular weight of only 503 and IC50 values of 23 and 20 nM in a human plasma renin assay at pH 6.0. Their very low aqueous solubility limited their further evaluation. The efficacy of these P2-P3 replacements is a result of their ability to maintain the important hydrogen-bonds with the enzyme. Due to conformational differences with the dipeptide, adjustment at the P2 side chain was required. These 4,5- and 3,5-dihydroxyhexanamide segments could be seen as novel N-terminal dipeptide replacements.
Subject(s)
Amides/chemical synthesis , Protease Inhibitors/chemical synthesis , Renin/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Humans , Indicators and Reagents , Kinetics , Molecular Conformation , Molecular Structure , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Renin/blood , Solubility , Stereoisomerism , Structure-Activity RelationshipSubject(s)
Community Health Centers/organization & administration , Adolescent , Adult , Female , Humans , QuebecABSTRACT
Since 1979, the Child Life Department of the Children's Hospital of Eastern Ontario has provided 75 hours per week of Child Life intervention for children and parents in the emergency department. Factors that would influence a child's ability to master an emergency experience have been identified through a review of the literature. The protocol for Child Life intervention in frequent emergency situations is described. Practical approaches to Child Life programs in Emergency and evaluation of effects of Child Life intervention are discussed.
Subject(s)
Child, Hospitalized/psychology , Emergency Service, Hospital , Child , Child, Preschool , Humans , OntarioABSTRACT
The purpose of this study was to determine whether physicians practicing in one type of setting manage a medical problem differently than those practicing in another type of setting. The investigation took the form of presenting physicians with a simulated case of tension headache with a history going back three years, for which diazepam had been taken daily for the past year. Four simulated patients (aged 20-23) visited a stratified random sample of 111 general practitioners practicing in health centers funded by government (CLSCs) and in private group practice clinics in the Montreal area. Fifty-one per cent of group practice physicians recommended therapy rated as "inadequate" compared to 25 per cent in CLSCs; in addition, the data show significant differences between CLSC and group practice physicians in performing various aspects of the clinical examination. Alternative explanations for the observed differences are discussed.
