Studies on Aromatase Inhibitors IV. Synthesis and Biological Evaluation of N,N-Disubstituted-5-aminopyrimidine Derivatives.

Okada, Minoru; Yoden, Toru; Kawaminami, Eiji; Kudou, Masafumi; Isomura, Yasuo

doi:10.1248/cpb.45.1293

Cited by 11 publications

(6 citation statements)

References 2 publications

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“…A common structural feature of these non-steroidal inhibitors is the presence of a sterically non-hindered heteroatom which coordinates the heme iron of the cytochrome P450 [1,[13][14][15][16][17][18]. Aminglutethimide (AG), a rather weakly potent "first generation inhibitor", was used with success in the treatment of patients with advanced breast cancer, but suffered from a poor selectivity with respect to other P450 enzymes.…”

Section: Mechanism and Types Of Inhibitionmentioning

confidence: 99%

“…The two most advanced "third generation inhibitors" are represented by Anastrozole [19] and Letrozole [20]. Others like YM511 [14,15] or CHAG [16] are highly active as well, but were abandoned because of market competitive reasons.…”

Section: Mechanism and Types Of Inhibitionmentioning

confidence: 99%

“…Very close analogues of YM511 [14,15] were prepared in the series of compounds according to Fig. (4), where the 1,2,4-triazole moiety is replaced by an imidazole ring [25].…”

Section: Deoxycortisolmentioning

confidence: 99%

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Inhibitors of Steroidal Cytochrome P450 Enzymes as Targets for Drug Development

Baston¹,

Leroux

2007

PRA

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Cytochrome P450's are enzymes which catalyze a large number of biological reactions, for example hydroxylation, N-, O-, S- dealkylation, epoxidation or desamination. Their substrates include fatty acids, steroids or prostaglandins. In addition, a high number of various xenobiotics are metabolized by these enzymes. The enzyme 17alpha-hydroxylase-C17,20-lyase (P450(17), CYP 17, androgen synthase), a cytochrome P450 monooxygenase, is the key enzyme for androgen biosynthesis. It catalyzes the last step of the androgen biosynthesis in the testes and adrenal glands and produces androstenedione and dehydroepiandrosterone from progesterone and pregnenolone. The microsomal enzyme aromatase (CYP19) transforms these androgens to estrone and estradiol. Estrogens stimulate tumor growth in hormone dependent breast cancer. In addition, about 80 percent of prostate cancers are androgen dependent. Selective inhibitors of these enzymes are thus important alternatives to treatment options like antiandrogens or antiestrogens. The present article deals with recent patents (focus on publications from 2000 - 2006) concerning P450 inhibitor design where steroidal substrates are involved. In this context a special focus is provided for CYP17 and CYP19. Mechanisms of action will also be discussed. Inhibitors of CYP11B2 (aldosterone synthase) will also be dealt with.

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Section: Mechanism and Types Of Inhibitionmentioning

confidence: 99%

Section: Mechanism and Types Of Inhibitionmentioning

confidence: 99%

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Inhibitors of Steroidal Cytochrome P450 Enzymes as Targets for Drug Development

Baston¹,

Leroux

2007

PRA

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“…An extensive work of structural modification was described, which regarded the azole and benzyl moieties, and at a lesser extent the phenyl substituent. [68][69][70][71] The two compounds selected for in depth evaluation, 15 (IC 50 ¼ 0.12 nM 71 ) and 16 (IC 50 ¼ 0.04 nM 68 ), maintained the quite relevant level of potency that poses them at the top of the list of most active NSAIs known up to date. A good selectivity was also claimed for 15 and 16, evaluated in in vitro cellular assays by testing the inhibition of the synthesis of other steroids (aldosterone, cortisol, testosterone).…”

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confidence: 99%

Nonsteroidal aromatase inhibitors: Recent advances

Recanatini

Cavalli

Valenti

2002

Medicinal Research Reviews

106

102

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Aromatase is the cytochrome P450 enzyme responsible for the last step of estrogen biosynthesis, and aromatase inhibitors constitute an important class of drugs in clinical use for the treatment of breast cancer. Nonsteroidal aromatase inhibitors (NSAIs) are competitive inhibitors of aromatase, which bind to the enzyme active site by coordinating the iron atom present in the heme group of the P450 protein. Presently, third generation NSAIs are in use, and research efforts are being carried out both to identify new molecules of therapeutic interest and to clarify the mechanism of action. In this article, we present a survey of the compounds that have been recently reported as NSAIs, to provide a broad view on the general structure-activity relationships of the class. Moreover, starting from the current knowledge of the mechanistic aspects of aromatase action and from recent theoretical work on the molecular modeling of both enzyme and inhibitors, we try to indicate a way to integrate these different studies in view of a more general understanding of the aromeatase-inhibitor system. Finally, some aspects regarding the possible future development of the field are considered briefly.

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“…A common treatment for estrogen‐dependent cancers is the use of antiestrogens and/or aromatase inhibitors [4]. The usual way to develop new aromatase inhibitors is to screen in vitro chemical compounds [5–10] from the knowledge of the substrate structure, or by comparisons with other aromatases [11–13]. The design of more specific and efficient aromatase inhibitors could be improved by a better knowledge of the enzyme's active site.…”

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confidence: 99%

Study of substrate specificity of human aromatase by site directed mutagenesis

Auvray

Nativelle

Bureau³

et al. 2002

European Journal of Biochemistry

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Human aromatase is responsible for estrogen biosynthesis and is implicated, in particular, in reproduction and estrogen-dependent tumor proliferation. The molecular structure model is largely derived from the X-ray structure of bacterial cytochromes sharing only 15-20% identities with hP-450arom. In the present study, site directed mutagenesis experiments were performed to examine the role of K119, C124, I125, K130, E302, F320, D309, H475, D476, S470, I471 and I474 of aromatase in catalysis and for substrate binding. The catalytic properties of mutants, transfected in 293 cells, were evaluated using androstenedione, testosterone or nor-testosterone as substrates. In addition, inhibition profiles for these mutants with indane or indolizinone derivatives were obtained. Our results, together with computer modeling, show that catalytic properties of mutants vary in accordance with the substrate used, suggesting possible differences in substrates positioning within the active site. In this respect, importance of residues H475, D476 and K130 was discussed. These results allow us to hypothesize that E302 could be involved in the aromatization mechanism with nor-androgens, whereas D309 remains involved in androgen aromatization. This study highlights the flexibility of the substrate-enzyme complex conformation, and thus sheds new light on residues that may be responsible for substrate specificity between species or aromatase isoforms.Keywords: aromatase; site-directed mutagenesis; molecular modeling; androgens; inhibitors.Estrogens are known to be implicated in reproduction and estrogen-dependent tumor proliferation [1]. Moreover, an abnormal expression of aromatase, the enzyme involved in the conversion of androgens to estrogens, has been detected in breast tumors and in surrounding adipose stromal cells [2,3]. The aromatase enzyme comprises a specific cytochrome P-450 aromatase and the ubiquitous cytochrome P-450 NADPH reductase. A common treatment for estrogen-dependent cancers is the use of antiestrogens and/or aromatase inhibitors [4]. The usual way to develop new aromatase inhibitors is to screen in vitro chemical compounds [5][6][7][8][9][10] from the knowledge of the substrate structure, or by comparisons with other aromatases [11][12][13]. The design of more specific and efficient aromatase inhibitors could be improved by a better knowledge of the enzyme's active site. A precise modeling of this part of the molecule is therefore necessary. Despite success in obtaining aromatase purified to homogeneity [14], crystallization of this microsomal membrane-anchored protein has not been reported. Knowledge of the aromatase structure is largely derived from comparisons with soluble bacterial cytochromes Pseudomons putida camphor P-450 (P-450cam), Bacillus megaterium P-450 (P-450BM-3), Pseudomonas putida a-terpineol P-450 (P-450terp) and Saccharopolyspora erythreae erythromycin F P-450 (P-450eryF), these proteins being well characterized and crystallized [15][16][17][18][19]. However, human aromatase shares only 15-20% ...

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Studies on Aromatase Inhibitors IV. Synthesis and Biological Evaluation of N,N-Disubstituted-5-aminopyrimidine Derivatives.

Cited by 11 publications

References 2 publications

Inhibitors of Steroidal Cytochrome P450 Enzymes as Targets for Drug Development

Inhibitors of Steroidal Cytochrome P450 Enzymes as Targets for Drug Development

Nonsteroidal aromatase inhibitors: Recent advances

Study of substrate specificity of human aromatase by site directed mutagenesis

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