甾体类芳香酶抑制剂的构效关系与研究进展

芳香醇是研究抗乳腺癌药物的新靶酶。本文从作用机制、构效关系等方面综述了甾体芳香酶抑制剂的研究进展。     

Substituted pyridines: nonsteroidal inhibitors of human placental aromatase cytochrome P-450.

The binding to human placental aromatase cytochrome P-450 and resulting extent of inhibition was examined for pyridine, pyridines substituted at the 2-, 3-, or 4-positions with phenyl or benzoyl groups, and the nonpyridinic structural analogs biphenyl and benzophenone. Spectral binding studies with partially purified aromatase indicated that pyridine, 3- and 4-phenylpyridines, and 3- and 4-benzoylpyridines interact at the active site via ligation of the pyridinic nitrogen to heme iron, as judged by the type II difference spectra. The apparent dissociation constants for these compounds are 2.1, 0.11, 0.09, 2.6, and 0.27 mM, respectively. Biphenyl, benzophenone, and 2-benzoylpyridine show exclusively a hydrophobic interaction in the presence of the substrate, androst-4-ene-3,17-dione, to give reverse type I difference spectra, with apparent spectral dissociation constants of 0.14, 0.42, and 1.8 mM, respectively. 2-Phenylpyridine shows a unique spectrum, previously not observed with cytochrome P-450, that has components of both type I and type II spectra. As measured by tritium ion release from [1 beta-3H]androst-4-ene-3,17-dione, competitive inhibition of human microsomal aromatase activity was observed with pyridine, 2-, 3-, and 4-phenylpyridines, biphenyl, and benzophenone, with Ki values of 320, 62, 1.48, 0.36, 750, and 130 microM, respectively. In contrast, 2-, 3-, and 4-benzoylpyridines exhibited complex kinetic behavior from which inhibition constants could not be obtained.(ABSTRACT TRUNCATED AT 250 WORDS)     

Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer

ABSTRACT

Background: Over the past few years, data have been published concerning the relative efficacy and safety profiles of tamoxifen and the aromatase inhibitors (AIs) in the adjuvant therapy setting for women with early hormone receptor-positive breast cancer. Recently, debate has centred around trials which have studied primary tamoxifen and AI therapy, switching and equencing strategies and extended adjuvant therapy.

Methods: Here, a group of 24 breast cancer experts review efficacy and safety data from the recent major trials investigating tamoxifen and the third-generation AIs in postmenopausal women, which have challenged the perception of tamoxifen as optimum adjuvant endocrine therapy. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, Breast International Group (BIG) 1‐98 study, National Cancer Institute of Canada MA 17 trial, Intergroup Exemestane Study (IES), Italian Tamoxifen Anastrozole (ITA) trial, Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8 and Arimidex-Nolvadex (ARNO) 95 are considered to provide a rational interpretation of the impact of these data on current practice, and to highlight areas where further investigation is needed.

Conclusion: We can be confident that AIs represent superior adjuvant endocrine treatment to tamoxifen in postmenopausal women, either as initial therapy or as an alternative for women who have started adjuvant therapy with tamoxifen. However, there remain issues regarding the best way to use AIs, such as the optimal length of AI treatment and how a sequence of tamoxifen followed by an AI compares with AI monotherapy; these will require further data to resolve.     

Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer

BACKGROUND: Over the past few years, data have been published concerning the relative efficacy and safety profiles of tamoxifen and the aromatase inhibitors (AIs) in the adjuvant therapy setting for women with early hormone receptor-positive breast cancer. Recently, debate has centred around trials which have studied primary tamoxifen and AI therapy, switching and sequencing strategies and extended adjuvant therapy. METHODS: Here, a group of 24 breast cancer experts review efficacy and safety data from the recent major trials investigating tamoxifen and the third-generation AIs in postmenopausal women, which have challenged the perception of tamoxifen as optimum adjuvant endocrine therapy. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, Breast International Group (BIG) 1-98 study, National Cancer Institute of Canada MA 17 trial, Intergroup Exemestane Study (IES), Italian Tamoxifen Anastrozole (ITA) trial, Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8 and Arimidex-Nolvadex (ARNO) 95 are considered to provide a rational interpretation of the impact of these data on current practice, and to highlight areas where further investigation is needed. CONCLUSION: We can be confident that AIs represent superior adjuvant endocrine treatment to tamoxifen in postmenopausal women, either as initial therapy or as an alternative for women who have started adjuvant therapy with tamoxifen. However, there remain issues regarding the best way to use AIs, such as the optimal length of AI treatment and how a sequence of tamoxifen followed by an AI compares with AI monotherapy; these will require further data to resolve.     

Pyridyl-substituted tetralone derivatives: a new class of nonsteroidal aromatase inhibitors]

Structural modification of flavone and flavanone, two weak inhibitors of aromatase, led to the new compounds 1-7, the syntheses of which are described as well as the evaluation of their aromatase and desmolase inhibitory potency. With the exception of 2 all compounds show a stronger inhibition of aromatase than the parent compounds and are more effective inhibitors than aminoglutethimide (AG), the only commercially available compound. In contrast to AG compounds 1 and 3-7 exhibit no desmolase inhibitory activity. In case of AG this effect leads to undesirable side effects.     

From nonsteroidal aromatase inhibitors to multifunctional drug candidates: classic and innovative strategies for the treatment of breast cancer

Aromatase is the enzyme responsible for the conversion of androgens to estrogens and represents the main source of local estrogens in post-menopausal breast cancer tissue. Nonsteroidal aromatase inhibitors (NSAIs) are able to reduce growth-stimulatory effects of estrogens in hormone-dependent breast cancer, and third generation NSAIs are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic advanced breast cancer. Nevertheless, some issues in this area still need to be addressed and research efforts are aimed both at identifying new molecules of therapeutic interest and at exploring different options for the modulation of this enzyme. In this review, an update of the latest developments in the field of NSAIs is presented, to provide a broad view on the recent progress in this area. Beside classical structure-activity relationships studies and development of natural product derivatives, rational approaches for both ligand- and structure-based design are described. Moreover, novel strategies for the development of multitarget-directed molecules are also presented. Finally, some possible future developments in this research area are briefly considered.     

Role of ribavirin in HCV treatment response: now and in the future

Importance of the field: Ribavirin is a broad spectrum antiviral agent that is used with pegylated IFN (Peg-IFN) for HCV treatment. Ribavirin does not significantly reduce HCV viral load when used alone but increases rates of sustained virologic response (SVR) when combined with Peg-IFN. HCV genotype 1 infected patients require higher doses of ribavirin administered for a longer duration of time versus HCV genotypes 2 and 3 patients who respond effectively to Peg-IFN with lower doses of ribavirin and shorter duration of therapy. Higher serum concentrations of ribavirin are associated with higher response rates but also higher rates of hemolytic anemia which is a dose limiting side effect. Alternatives to current therapy are under clinical evaluation.

Areas covered in this review: Systematic literature review of ribavirin use in HCV patients from 1995 to 2009 was conducted.

What the reader will gain: To review the efficacy and safety of ribavirin in current HCV treatment and in new therapies in Phase III clinical trials.

Take home message: Ribavirin is a drug which is essential to produce higher SVR rates both with Peg-IFN and HCV protease inhibitors currently in Phase III clinical trials. Thus, ribavirin is and will remain an important drug to achieving higher SVR rates in HCV infected persons.     

Novel cholinesterase inhibitors as future effective drugs for the treatment of Alzheimer's disease

Current pharmacotherapy for Alzheimer's disease involves compounds that are aimed at increasing the levels of acetylcholine in the brain by facilitating cholinergic neurotransmission through inhibition of cholinesterase. These drugs, known as acetylcholinesterase inhibitors, have been shown to improve cognition and global functions but have little impact on improving the eventual progression of the disease; however, there is evidence that other cholinesterases such as butyrylcholinesterase can play an important role in cholinergic function in the brain, and the long-suspected non-cholinergic actions of acetylcholinesterase, mainly the interference with the beta-amyloid protein cascade, have recently driven a profound revolution in cholinesterase drug research. Several disease-modifying agents are under development that target these enzymes and have hope of becoming the next generation of effective drugs in the treatment of Alzheimer's disease.     

New structure-activity relationships of A- and D-ring modified steroidal aromatase inhibitors: design, synthesis, and biochemical evaluation

A- and D-ring androstenedione derivatives were synthesized and tested for their abilities to inhibit aromatase. In one series, C-3 hydroxyl derivatives were studied leading to a very active compound, when the C-3 hydroxyl group assumes 3β stereochemistry (1, IC(50) = 0.18 μM). In a second series, the influence of double bonds or epoxide functions in different positions along the A-ring was studied. Among epoxides, the 3,4-epoxide 15 showed the best activity (IC(50) = 0.145 μM) revealing the possibility of the 3,4-oxiran oxygen resembling the C-3 carbonyl group of androstenedione. Among olefins, the 4,5-olefin 12 (IC(50) = 0.135 μM) revealed the best activity, pointing out the importance of planarity in the A,B-ring junction near C-5. C-4 acetoxy and acetylsalicyloxy derivatives were also studied showing that bulky substituents in C-4 diminish the activity. In addition, IFD simulations helped to explain the recognition of the C-3 hydroxyl derivatives (1 and 2) as well as 15 within the enzyme.     

Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease.

A new class of potent, selective, nonsteroidal inhibitors of aromatase have been discovered. The most potent member of this series is fadrozole hydrochloride, CGS 16949 A, 4-(5,6,7,8-tetrahydroimidazo[1,5-alpha]pyridin-5-yl)benzonitrile monohydrochloride, 26a. In addition, the 6,7-dihydropyrrolo[1,2-c]imidazole (21a) and the 6,7,8,9-tetrahydroimidazo[1,5-alpha]azepine (21b) analogues were synthesized and evaluated. CGS 16949 A's ability to selectively inhibit aromatase (IC50 = 4.5 nM) over other cytochrome P-450 enzymes and suppress estrogen production when administered orally make it a suitable candidate to test the potential of an aromatase inhibitor in estrogen-dependent diseases including breast cancer.