Pyrazolo[3,4-]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 1: 4-acylamino derivatives.

The synthesis of a new series of 4-acylaminopyrazolo[3,4-]pyrimidines active on the sigma-1 receptor (σR) is reported. Compounds were efficiently prepared using a two to three step process starting from commercially available 1-pyrazolo[3,4-]pyrimidin-4-amine. A SAR study shows that the σR requires the presence of relatively highly lipophilic substituents at opposite sides of the central scaffold, while selectivity the σR can be improved by shortening the distance of the basic nitrogen to it.

Synthesis and biological evaluation of the 1-arylpyrazole class of σ(1) receptor antagonists: identification of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862).

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores.

Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors.

Anti-inflammatory efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has been related to their properties as inhibitors of cyclooxygenase (COX)-mediated prostaglandin (PG) synthesis. However, recent studies have suggested that variations of the in vivo anti-inflammatory actions among different NSAIDs could not be solely explained by COX inhibition. Here, we have analyzed the effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole anti-inflammatory drugs with different potencies as COX-2 inhibitors, namely E-6087, E-6232, E-6231, E-6036 and E-6259 as well as the chemically related COX-2 inhibitor Celecoxib.

Factors influencing prognosis after neo-adjuvant chemoradiation therapy for rectal carcinoma.

Background: Neo-adjuvant chemoradiation therapy (CRTx) has become a standard therapeutic regimen for rectal carcinoma. This therapeutic option allows more sphincter preserving surgical procedures and seems to improve prognosis in patients with rectal carcinoma. The aim of this study is to analyse factors influencing prognosis in terms of disease free survival (DFS) and overall survival (OS) after CRTx.

Factors influencing histological response after neoadjuvant chemoradiation therapy for rectal carcinoma.

Neoadjuvant chemoradiation therapy is one of the standard therapeutic regimens for rectal carcinoma. Nevertheless, chemoradiation therapy is not completely devoid of adverse effects, and it would be interesting to try to predict which patient will respond to neoadjuvancy. This study aimed at analyzing factors influencing pathological response after therapy.