ABSTRACT
A novel series of 1-sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists was discovered through high throughput screening (HTS) and medicinal chemistry lead optimization. Potency and in vivo properties were systematically optimized to afford orally bioavailable, highly efficacious, and selective CB1R inverse agonists that caused food intake suppression and body weight reduction in diet-induced obese rats and dogs. It was found that the receptor binding assay predicted in vivo efficacy better than functional antagonist/inverse agonist activities. This observation expedited the structure-activity relationship (SAR) analysis and may have implications beyond the series of compounds presented herein.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Piperazines/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfonamides/chemical synthesis , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Biological Availability , Body Weight/drug effects , Dogs , Drug Inverse Agonism , Eating/drug effects , Hepatocytes/metabolism , Humans , In Vitro Techniques , Macaca mulatta , Microsomes, Liver/metabolism , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologySubject(s)
Bioterrorism/prevention & control , Disaster Planning/organization & administration , Military Medicine/organization & administration , Security Measures/organization & administration , Anthrax/prevention & control , Health Policy/trends , Humans , Plague/prevention & control , Public Health Practice , Smallpox/prevention & control , United StatesABSTRACT
The U.S. Air Force Academy (USAFA) is one of the nation's military universities, with the mission to educate and motivate cadets to be career Air Force officers. This diverse population arrives at the USAFA with varying immunization records and disease histories. Analyses of costs and benefits regarding immunization strategies rely on accurate data and assumptions used in their calculation. Health history questionnaires are a low-cost way of evaluating immunization and disease history. However, this requires a good estimate of the questionnaire's positive predictive value, which may vary among populations. This study attempts to provide a more accurate estimate of the positive predictive value of health history questionnaires regarding varicella and rubella disease and vaccination strategies for the population of fourth degree (freshman) cadets at the USAFA. We found positive predictive values of 99% for rubella and 86% for varicella. These data emphasize the importance of analyzing the specific population for which a program is intended rather than broadly applying recommendations that were developed in other populations.
