New steroids and steroid–longacting β2agonist combinations

New, highly selective, glucocorticoid receptor agonists based on an androstane 17β-carbothioate ester scaffold are claimed. Combinations of these steroids with novel long-acting β₂ agonists are also claimed. This patent defines potential replacements for fluticasone propionate and the combination of salmeterol and fluticasone propionate (Advair?, Glaxo Wellcome, Inc.).     

Subtype selective α1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is highly prevalent in the male population beyond the age of 60. Impairment of urinary flow due to prostate enlargement gives rise to symptoms of ‘prostatism’ that have a detrimental impact on the quality of life. The current trend in the management of symptomatic BPH favours pharmacotherapy as a first line option, while the number of surgical procedures being performed has experienced a steady decline during the last ten years. Among the pharmacological treatments, the use of α1-adrenoceptor blockers has demonstrated to be an effective treatment option for BPH. These agents reduce the adrenergic tone to the prostate and increase urinary flow, with a concomitant reduction of lower urinary tract symptoms. The α1-blockers currently approved include compounds such as alfuzosin, terazosin and doxazosin, originally developed for the treatment of hypertension, and more recently tamsulosin, an α1-subtype selective drug. The blockade of α1-adrenoceptors present in vascular smooth muscle is largely responsible for the most prominent side effects of current drugs, which can be severe and require patients dose titration. The limitation imposed by side effects naturally raises the possibility that complete blockade of prostatic α1 receptors is not attained at the maximum tolerated dose. The extensive efforts by the pharmaceutical industry towards the development of uroselective α1-blockers, is the subject of this review. Advances in the molecular cloning of genes encoding three α1-adrenoceptors led to the identification of the α1A-subtype as the predominant receptor responsible for the contraction of prostate smooth muscle. In preclinical animal models, selective α1A-antagonists have consistently been found to have minimal cardiovascular effects, thus providing a pharmacological rationale for uroselectivity. It has also become apparent, however, that uroselectivity can emerge in a poorly understood manner from the pharmacodynamic properties of compounds without α1A-subtype selectivity. Clinical experience with tamsulosin, an α1A/α1D selective drug, has failed to demonstrate a significant improvement in efficacy beyond that demonstrated for non-subtype selective α1-blockers, and gives support to the notion that α1A-selective antagonists might achieve greater efficacy for the treatment of BPH. Given the demonstrated uroselectivity of α1A-selective antagonists in preclinical models, it is anticipated that third generation α1-blockers will exhibit improved urinary flow efficacy and be better tolerated than tamsulosin. The extent to which the improvement in urinary flow will translate to the relief of symptoms of prostatism, however, remains to be demonstrated in randomised placebo-controlled clinical trials of α1A-selective antagonists.     

An inhaled VLA-4 antagonist

Dry powder, micronised formulations of a single peptidic VLA-4 antagonist are claimed. Their use is claimed to provide a method of treating asthma and other inflammatory diseases when administered via inhalation. The active ingredient of these formulations is deduced to be the clinical candidate GW-559090.     

COX-2 inhibitors

These three applications claim 4-fluoroalkyl-6-(4-alkylsulfonyl)phenylpyrimidine derivatives that are selective COX-2 inhibitors. The presence of an additional 5-alkyl substituent markedly attenuates their potency but both 4-alkylamino and 4-alkoxy substituted compounds are potent and selective COX-2 inhibitors in the absence of the 5-substituent.     

Epidermal growth factor receptor tyrosine kinase inhibitors

Activation of the epidermal growth factor receptor (EGFR) has been linked to tumour proliferation, invasion, metastasis and angiogenesis in epithelial tumours. Inhibitors of the EGFR have emerged as promising anticancer agents and two main approaches have been developed, humanised monoclonal antibodies and tyrosine kinase inhibitors. This review discusses the current status of EGFR tyrosine kinase inhibitors (EGFR-TKIs) that have entered clinical development. EGFR-TKIs are generally well tolerated and can sometimes produce impressive tumour regression in patients with advanced non-small-cell lung cancer. However, highly predictive or surrogate markers of activity have not been identified and there remains a need for translational research in their future development.