ABSTRACT
Lack of knowledge on the impact of infant development and behavior on breastfeeding affects both professionals and the clients they serve. Continuing education for Nevada WIC professionals with the online HUG Your Baby course Roadmap to Breastfeeding Success was implemented. This two-hour online course teaches about baby's development from birth to one year in relation to the breastfeeding journey. Tests and self-report surveys were used to evaluate these objectives pre- and post-intervention. Results showed significant improvement in knowledge about infant behavior and development, confidence in identifying and responding to infant behavior, and the positive integration of HUG resources into the professionals' work.
ABSTRACT
A number of known 1,4-dihydropyridine CCBs were identified as having comparable potency to the steroidal MR antagonist eplerenone. Chiral resolution of mebudipine revealed that MR and CCB activity reside in opposite enantiomers. Small molecule X-ray crystal structures showed that the C4 stereochemistry of optimized selective MR analogues, e.g. 5, is consistent with MR-active mebudipine. Molecular modeling supports a binding pose consistent with that previously proposed for DHP diesters.
Subject(s)
Dihydropyridines/chemistry , Mineralocorticoid Receptor Antagonists , Animals , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/metabolism , Cell Line , Crystallography, X-Ray , Dihydropyridines/pharmacology , Eplerenone , Genes, Reporter , Humans , Luciferases/genetics , Models, Molecular , Protein Binding , Rats , Receptors, Mineralocorticoid/chemistry , Receptors, Mineralocorticoid/genetics , Spironolactone/analogs & derivatives , Spironolactone/chemistry , Spironolactone/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-1-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate (TC) in H14 cells. A 3R,4R,5R/3S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Benzothiepins/chemical synthesis , Bile Acids and Salts/metabolism , Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors , Symporters/antagonists & inhibitors , Animals , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Benzothiepins/chemistry , Benzothiepins/pharmacology , Biological Availability , Cell Line , Cricetinae , Crystallography, X-Ray , Humans , Magnetic Resonance Spectroscopy , Male , Mesocricetus , Rats , Stereoisomerism , Structure-Activity Relationship , Taurocholic Acid/metabolismABSTRACT
In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.
