Novel CYP17 inhibitors: Synthesis, biological evaluation, structure–activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls

Hille, Ursula; Hu, Qingzhong; Vock, Carsten A.; Negri, Matthias; Bartels, Marc; Müller‐Vieira, Ursula; Lauterbach, Thomas; Hartmann, Rolf W.

doi:10.1016/j.ejmech.2009.01.002

Cited by 68 publications

(29 citation statements)

References 34 publications

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“…Mineralocorticoid excess is currently prevented by the co-administration of dexamethasone [55 •• ]. The success of abiraterone acetate has led to the development of both steroidal and nonsteroidal inhibitors of this enzyme [59, 60 •• ]. One such compound VN/124-1 not only inhibits the target enzyme but also increases the rate of AR degradation [60 •• ].…”

Section: Targeting the Androgen Axes In Prostate Diseasementioning

confidence: 99%

New frontiers in androgen biosynthesis and metabolism

Penning

2010

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review To summarize recent advances in androgen biosynthesis and metabolism in peripheral tissues (e.g. liver and prostate) and how these can be exploited therapeutically. Recent findings Human liver catalyzes the reduction of circulating testosterone (T) to yield four stereoisomeric tetrahydrosteroids. Recent advances have assigned the enzymes responsible for these reactions and elucidated their structural biology. Data also suggests that for 5α-dihydrotestosterone (5α-DHT), conjugation reactions (phase II) may precede ketosteroid reduction (phase I) reactions. Human prostate is the site of benign prostatic hyperplasia and prostate cancer which occur in the aging male. While the importance of local androgen biosynthesis in these diseases is accepted, recent advances have identified enzymes that regulate ligand access to the androgen receptor; a “backdoor pathway” to 5α-DHT that does not require T acting as an intermediate; and the finding that castrate resistant prostate cancer has undergone an adaptive response to androgen deprivation, which involves intra-tumoral T and 5α-DHT biosynthesis that can be targeted using inhibitors of (CYP17-hydroxylase/17,20-lyase), aldo-keto reductase 1C3, and 5α-reductase type 1 and type 2. Summary Enzyme isoforms responsible for the biosynthesis and metabolism of androgens in liver and prostate have been identified and those responsible for the biosynthesis of androgens in castrate resistant prostate cancer can be therapeutically targeted.

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Section: Targeting the Androgen Axes In Prostate Diseasementioning

confidence: 99%

New frontiers in androgen biosynthesis and metabolism

Penning

2010

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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“…[8] As a novel promising approach, inhibition of aldosterone biosynthesis by selective inhibition of CYP11B2 was proposed by our group. [9] Utilizing the long experience gained in the development of inhibitors of different CYP enzymes, such as hCYP17, [10][11][12][13][14][15][16][17][18] hCYP19 [19][20][21][22] and hCYP11B1, [23][24][25] assay development and biological screening of a library of CYP inhibitors yielded the first hit compounds. [26] Subsequent optimization resulted in several classes of nonsteroidal highly potent hCYP11B2 inhibitors, i.e.…”

Section: Introductionmentioning

confidence: 99%

Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase

Grombein¹,

Hu²,

Rau³

et al. 2015

European Journal of Medicinal Chemistry

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CitationHeteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase. AbstractAldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11Binhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 2 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC 50 < 1 nM) and the corresponding rat enzyme (4: 64 %, 9: 51 % inhibition, at 2 µM). Abbreviations

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“…As summarized in Table 2, 8,9,[13][14][15] it has been reported that the IC 50 value of abiraterone, which also contains a hydroxyl group at C 3 in the A ring and a double bond at C 5 in the B ring, was 0.072 µM.…”

Section: Fig 2 Inhibitory Effect Of 21-hydroxypregnenolone On Humanmentioning

confidence: 99%

Inhibition of Human Steroidogenic Cytochrome P450 c17 by 21-Hydroxypregnenolone and Related Steroid Hormones

Niwa

Imamura

Katagiri

2012

Biological & Pharmaceutical Bulletin

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The effects of 21-hydroxypregnenolone and related steroids such as deoxycorticosterone (DOC; 21-hydroxyprogesterone), cortisol, and corticosterone on progesterone 17α-hydroxylase activity by steroidogenic cytochrome P450 c17 (CYP17) were investigated. 21-Hydroxypregnenolone contains a hydroxyl group at C 3 in the A cyclic hydrocarbon ring and a double bond at C 5 in the B cyclic hydrocarbon ring, whereas DOC, cortisol, and corticosterone contain a ketone group at C 3 and a double bond at C 4 in the A cyclic hydrocarbon ring. No marked inhibition was observed for DOC, cortisol, and corticosterone at 100 μM concentration. Nonetheless, 21-hydroxypregnenolone exhibited competitive inhibition of progesterone 17α-hydroxylation activity by CYP17 with a K i value of 36.4 µM. These results suggest that a hydroxyl group at C 3 in the A ring and a double bond at C 5 in the B ring in steroid hormones are important for the substrate recognition of CYP17.Key words cytochrome P450 c17; 21-hydroxypregnenolone; 17α-hydroxylation; deoxycorticosterone; corticosterone; progesterone Cytochrome P450 c17 (CYP17) is found in the endoplasmic reticulum of the adrenal cortex and gonads, and mediates both 17α-hydroxylase and 17,20-lyase reactions of pregnenolone and progesterone, thus being involved in the biosynthesis of glucocorticoids and sex hormones. 1)Various steroid hormones are biotransformed by metabolic enzymes including CYP11 and CYP21 as well as CYP17, in adrenal glands (Fig. 1). Deoxycorticosterone (DOC; 21-hydroxyprogesterone), cortisol, and corticosterone are well known to be important in the principal pathways of steroid hormone synthesis.2) 21-Hydroxypregnenolone has been shown to be biotransformed from pregnenolone in human, rat, and sheep adrenal tissue in vitro, 3,4) although how 21-hydroxypregnenolone is formed in human tissues or organs remains unknown. 21-Hydroxypregnenolone is detectable in urine of newborn human infants 5) and adults, 6) and 21-hydroxypregnenolone excretion is highly elevated in 21-hydroxylase deficiency.7) 21-Hydroxypregnenolone contains a hydroxyl group at C 3 in the A cyclic hydrocarbon ring and a double bond at C 5 in the B cyclic hydrocarbon ring, whereas DOC, cortisol, and corticosterone contain a ketone group at C 3 and a double bond at C 4 in the A ring. In particular, DOC is identical to 21-hydroxypregnenolone except at C 3 , C 4 , and C 5 positions. Thus there is a possibility that biotransformed steroid hormones might affect human steroidogenesis in the adrenal gland.We previously demonstrated that endocrine disrupters such as bisphenol A and nonylphenol exhibited competitive inhibition of progesterone 17α-hydroxylation by human CYP17. 8,9) In the present study we investigated the inhibitory effects of 21-hydroxypregnenolone, DOC, cortisol, and corticosterone on catalytic activity of recombinant human CYP17 expressed in Escherichia coli membrane fractions.

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Novel CYP17 inhibitors: Synthesis, biological evaluation, structure–activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls

Cited by 68 publications

References 34 publications

New frontiers in androgen biosynthesis and metabolism

New frontiers in androgen biosynthesis and metabolism

Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase

Inhibition of Human Steroidogenic Cytochrome P450 c17 by 21-Hydroxypregnenolone and Related Steroid Hormones

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