Potent Long-Acting Inhibitors Targeting the HIV-1 Capsid Based on a Versatile Quinazolin-4-one Scaffold.

Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro, are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs.

Unexpected effects of cognitive-behavioural therapy on self-reported exercise behaviour and functional outcomes in older adults.

BACKGROUND: nearly 61% of older adults do not maintain recommended exercise levels emphasising the need for interventions that promote exercise. OBJECTIVES: to compare self-reported exercise behaviour and functional outcomes over 1 year across three groups of older adults: a cognitive-behavioural therapy group, an attention-control education group and a control group. DESIGN: randomised intervention. SETTING: community exercise facilities. PARTICIPANTS: three hundred and thirty-two older adults (mean age = 71.8 ± 5.1 years). METHODS: all three groups received exercise training three times per week for 2 weeks and then one time per week for 8 weeks, during which time the therapy and education groups received their interventions. Blinded data collectors measured follow-up exercise behaviour and functional outcomes at 3-month intervals. RESULTS: after controlling for previous year exercise behaviour, results showed that relative to the control group, the therapy and education groups increased their strengthening exercises over time (0.05 and 0.06 h/week higher, respectively); only the therapy group's change was significant. Also, relative to the control group, the therapy and education groups significantly reduced their 6-min walking distances over time (-1.6 m, P = 0.030 and -1.5 m, P = 0.026, respectively). CONCLUSIONS: although the therapy group increased their strength training, they reduced their 6-min walking distance.

Cognitive-behavioral therapy, exercise, and older adults' quality of life.

This study examined health-related quality of life (HRQL) at baseline and 6, 9, and 12 months after initiating exercise training in three groups of older adults. The conditions were cognitive-behavioral therapy, attention-control health promotion education, and a control group. Participants (N = 332) were mainly women (n = 252, 75.9%) with a mean age of 71.8 (SD = 5.1) years. Therapy participants were trained to modify their negative interpretations of exercise. Participants in the education group received information unrelated to exercise. After controlling for exercise behavior over time, the therapy group reported lower general health, more role limitations because of emotional problems, and somewhat less vitality than the control group did. The education group also reported lower general health and vitality than the control group did. Social interaction and discussion may heighten participants' awareness of these health aspects and influence their appraisal of HRQL. Findings demonstrate the complexities of HRQL and the challenge in developing effective methods for helping older adults adopt and maintain an active lifestyle.

4,5-Disubstituted cis-pyrrolidinones as inhibitors of type II 17beta-hydroxysteroid dehydrogenase. Part 3. Identification of lead candidate.

A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.

Cognitive behavioral therapy to promote exercise behavior in older adults: implications for physical therapists.

Although exercise has both physical and psychological benefits, most older adults do not exercise on a regular basis. Physical therapists need to explore ways to encourage sustained commitment. This article proposes that cognitive factors contribute to older adults inactivity and that the self regulation of exercise maintenance model is a means of promoting exercise. Cognitive behavioral therapy (CBT), an intervention guided by the self-regulation model, is presented as a practical way to help older adults see how thoughts guide their exercise behavior. The article concludes with a hypothetical case in which principles of CBT are used to promote exercise with older adults.

Planning psychoeducational groups for older adults.

Psychoeducational group work, with its focus on education and psychological growth, is a versatile and effective method of teaching older adults new skills and behaviors. Planning a psychoeducational group should be systematic and well thought out. Each session outline should include objectives, information to be imparted, life-skill experiential activities, and process questions to make the connection between the information and the experience.

Integration of optimized substituent patterns to produce highly potent 4-aryl-pyridine glucagon receptor antagonists.

Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.

Discovery of 5-hydroxyalkyl-4-phenylpyridines as a new class of glucagon receptor antagonists.

5-Hydroxyalkyl-4-phenylpyridines have been identified as a novel class of glucagon antagonists with potential utility for the treatment of diabetes. A lead structure with moderate activity was discovered through a high throughput screening assay. Structure-activity relationships led to the discovery of a potent antagonist, IC(50)=0.11 microM, more than 60-fold improvement over the lead structure.