N-hydroxy-3-phenyl-2-propenamides as novel inhibitors of human histone deacetylase with in vivo antitumor activity: discovery of (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824).

A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC(50) < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD > or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.

Learning disabilities and the menopause.

How menopause affects women with learning disabilities is a neglected area of research. Women with learning disabilities experience the same physiological effects of the menopause as others, including hot flushes and night sweats, but difficulties in understanding and communication mean that additional supports are often required. They are less likely to report the psychological difficulties or symptoms associated with menopause than women in the general population. Menopause is usually earlier in women with learning disability and earlier still for those with Down's syndrome. Debate about hormone replacement therapy often ignores the needs of women with learning disabilities who, as a result, are very often excluded from the decision-making process. Physical problems among women with learning disabilities and other aspects of ageing warrant particular focus.