2-Pyridyl P1'-substituted symmetry-based human immunodeficiency virus protease inhibitors (A-792611 and A-790742) with potential for convenient dosing and reduced side effects.

A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.

An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists.

The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.

Antidiabetic activity of passive nonsteroidal glucocorticoid receptor modulators.

Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.

Development of potentially better practices for the neonatal intensive care unit as a culture of collaboration: communication, accountability, respect, and empowerment.

OBJECTIVE: The Vermont Oxford Network (VON) CARE Group was formed in response to the need to create organizational cultures supportive of change and quality improvement. METHODS: The CARE Group consisted of team members from 4 participating neonatal intensive care units (NICUs). All CARE Group members chose to work on multidisciplinary teamwork for the duration of the Neonatal Intensive Care Quality Improvement Collaborative Year 2000. A questionnaire was developed by the CARE Group and administered to the 4 focus group NICUs. The survey focused on 6 domains of the organization: unit coordination, working in the NICU, leadership, management of disagreements, authority, and unit culture. Benchmarking visits were completed to supplement the information found in the survey and the literature. RESULTS: Seven potentially better practices (PBPs) were developed on the basis of the surveys, benchmark visits, and literature reviews. The PBPs include 1) a clear, shared NICU purpose, goals, and values; 2) effective communication among and between teams and team members; 3) leaders lead by example; 4) nurture a collaborative NICU environment with trust and respect; 5) live principled standards of conduct and standards of excellence; 6) nurture competent and committed teams and team members; and 7) commit to effective and positive conflict management. CONCLUSIONS: The CARE Group successfully used quality improvement methods and collaboration to delineate principles and practices of multidisciplinary teamwork.

Factors affecting the delivery of HIV/AIDS prevention programs by community-based organizations.

Community based organizations (CBOs) play a frontline role in HIV/AIDS prevention activities. CBOs face formidable challenges to effective delivery of HIV prevention services including client characteristics such as homelessness and CBO characteristics such as limited resources and staff turnover. Despite these obstacles, CBOs are generally well positioned to deliver services to specific high-risk populations because they understand their local communities and are connected to the groups they serve. [C1]This qualitative study illustrates that structural, sociocultural, organizational, and individual client factors both facilitate and act as barriers to delivery of HIV prevention services. These challenges and successes help identify critical technical assistance needs.