Progress in the development of ß-lactams as N-Acylethanolamine Acid Amidase (NAAA) inhibitors: Synthesis and SAR study of new, potent N-O-substituted derivatives.

The anti-inflammatory effects resulting from raising the levels of palmitoylethanolamide (PEA), an endogenous bioactive lipid, led to envisage N-Acylethanolamine Acid Amidase (NAAA), the cysteine hydrolase mainly responsible for PEA degradation, as an attractive target for small molecule inhibitors. Previous work in our group identified serine-derived ß-lactams as potent and systemically active inhibitors of NAAA activity. Aiming to expand the SAR study around this class of compounds, we investigated the effect of the substitution on the endocyclic nitrogen by designing and synthesizing a series of N-substituted ß-lactams. The present work describes the synthesis of new N-O-alkyl and N-O-aryl substituted ß-lactams and reports the results of the structure activity relationship (SAR) study leading to the discovery of a novel, single-digit nanomolar NAAA inhibitor (37). Compound 37 was shown in vitro to inhibit human NAAA via S-acylation of the catalytic cysteine, and to display very good selectivity vs. human Acid Ceramidase, a cysteine amidase structurally related to NAAA. Preliminary in vivo studies showed that compound 37, administered topically, reduced paw edema and heat hyperalgesia in a carrageenan-induced inflammation mouse model. The high in vitro potency of 37 as NAAA inhibitor, and its encouraging in vivo activity qualify this compound as a new tool for the study of the role of NAAA in inflammatory and pain states.

Combating HIV in Africa: a role for economic research.

PIP: HIV infection has been shown to be associated with substantial costs in many sectors of the economy. This finding has helped to bring attention to the epidemic in Africa and convince policymakers outside of the health sector about the serious threat posed by HIV/AIDS. Limited evidence indicates that the prevention of HIV infection is among the top health priorities in any African country with a significantly high incidence of infection. Additional research on the secondary economic effects of HIV infection is needed to further define the benefit associated with preventing a case, but that should no longer be the primary focus of research upon the economic aspects of HIV infection in Africa. Priority should instead shift to the evaluation of the cost-effectiveness of interventions to reduce HIV transmission, interventions to reduce HIV transmission, interventions to treat HIV-related disease, and interventions to reduce the negative impact upon survivors. Sections consider the benefit of preventing HIV infection versus other diseases, the benefit of preventing a case of HIV infection, the benefit associated with preventing secondary cases, the benefit associated with preventing secondary poverty, benefits of preventing different types of HIV infection, the cost of preventing a case of HIV infection, and the cost of preventing a case of HIV infection compared to other diseases.^ieng