Spiro[chromane-2,4'-piperidine]-based histone deacetylase inhibitors with improved in vivo activity.

A series of spiro[chromane-2,4'-piperidine] derivatives based on a previously published lead benzyl spirocycle 1 and bearing various N-aryl and N-alkylaryl substituents on the piperidine ring were prepared as novel histone deacetylase (HDAC) inhibitors. The compounds were evaluated for their abilities to inhibit nuclear HDACs, their in vitro antiproliferative activities, and in vitro ADME profiles. Based on these activities, 4-fluorobenzyl and 2-phenylethyl spirocycles were selected for further characterization. In vivo pharmacokinetic (PK) studies showed that both compounds exhibit an overall lower clearance rate, an increased half-life, and higher AUCs after intravenous and oral administration than spiropiperidine 1 under the conditions used. The improved PK behavior of these two compounds also correlated with superior in vivo antitumor activity in an HCT-116 xenograft model.

Termo do 1º Consenso em Disfunção Temporomandibular e Dor Orofacial / Statement of the 1st Consensus on Temporomandibular Disorders and Orofacial Pain

O Termo do 1º Consenso em Disfunção Temporomandibular e Dor Orofacial* foi criado com o propósito de substituir divergências por evidência científica dentro dessa especialidade da Odontologia. O documento oferece informações claras e fundamentadas para orientar o cirurgião-dentista e demais profissionais de saúde sobre os cuidados demandados pelo paciente, tanto no processo de diagnóstico diferencial quanto na fase de aplicação das terapias de controle da dor e disfunção. O Termo foi aprovado no mês de janeiro de 2010 em reunião realizada durante o Congresso Internacional de Odontologia do Estado de São Paulo e converge o pensamento dos profissionais mais conceituados do Brasil na especialidade Disfunção Temporomandibular e Dor Orofacial.

This Statement of the 1st Consensus on Temporomandibular Disorders and Orofacial Pain was created with the purpose of substituting controversies for scientific evidence within this specialty field of dentistry. The document provides clear and well-grounded guidance to dentists and other health professionals about the care required by patients both in the process of differential diagnosis and during the stage when they undergo treatment to control pain and dysfunction. The Statement was approved in January 2010 at a meeting held during the International Dental Congress of São Paulo and draws together the views of Brazil's most respected professionals in the specialty of Temporomandibular Disorders and Orofacial Pain.

Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors.

The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.

Evaluation of in vitro brain penetration: optimized PAMPA and MDCKII-MDR1 assay comparison.

Parallel artificial membrane permeability assay (PAMPA) is arising in ADMET screening as a powerful tool to determine the passive permeability of new potential chemical entities. In an attempt to set up a sensitive high throughput method to assess passive blood-brain barrier (BBB) penetration we focused our attention on the effect of solvent and the influence of phospholipids on the permeability in PAMPA. Moreover, the high throughput nature of the assay was maximized by decreasing the incubation time and performing the assay in a cassette mode. UPLC system coupled with a mass spectrometer enormously reduces the analytical time, contemporaneously increasing the sensitivity of the method. P(app) values obtained from PAMPA were compared to permeability values from MDCKII-MDR1 assay. Evaluation of the two in vitro models with in vivo data was performed to test the predicting capacity of the two methods. Their contemporary assessment was shown to be an helpful tool in understanding the prevalent mechanism of penetration through the BBB.