4,5‐Dihydro‐3‐(2‐pyrazinyl)naphtho[1,2‐<i>c</i>]pyrazole: A Potent and Selective Inhibitor of Steroid‐17α‐Hydroxylase‐C17,20‐Lyase (P450 17)

Hartmann, Rolf W.; Wächter, Gerald A.; Sergejew, T.; Würtz, Rieka; Düerkop, Jörg

doi:10.1002/ardp.19953280703

Cited by 28 publications

(14 citation statements)

References 25 publications

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“…The compounds also lowered serum testosterone (6) effectively in rats at 3 mg/kg to 14, 5 and 36% of control, respectively. Compound 97, 4,5-dihydro-3(2-pyrazinyl)naphto [1,2-c]pyrazole, displayed 10-fold more potent inhibition of the rat enzyme than ketoconazole (2) ( Table 6, entry 4) [206].…”

Section: Other Derivativesmentioning

confidence: 99%

CYP17 Inhibitors for Prostate Cancer Treatment – An Update

Moreira

Salvador²,

Vasaitis³

et al. 2008

CMC

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It is almost 70 years since the discovery by Huggins et al. that androgens are essential for prostate cancer (PC) growth and progression, and there has been about 30 years experience using ketoconazole for PC therapy. Since then we have come a long way in learning about the disease and developing new strategies to approach it, among which is cytochrome 17alpha-hydroxylase-C(17,20)-lyase (CYP17) inhibition. This review focuses on the efforts to find prospective CYP17 inhibitors, both steroidal and nonsteroidal, in the absence of a 3D structure of the enzyme. It covers almost 4 decades of literature with highlights on the most significant achievements in this area, providing insight into PC pathophysiology, management and treatment options.

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Section: Other Derivativesmentioning

confidence: 99%

CYP17 Inhibitors for Prostate Cancer Treatment – An Update

Moreira

Salvador²,

Vasaitis³

et al. 2008

CMC

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“…The enzyme in question is 17α-hydroxylase-C17,20-lyase (P450 17) which catalyzes the conversion of progesterone and pregnenolone into the androgens, androstenedione and dehydroepiandrosterone (DHEA), respectively [11,12] . Recently we have shown [6,13,14] that a dihydro-or tetrahydronaphthalene nucleus is able to give -after linkage with an N containing heterocycle such as imidazole, pyrazine, or pyridine -highly potent inhibitors of P450 17 (e.g., I and II, Chart 1 [6] ). While the heterocyclic N is complexing the heme iron of P450 17, the rest of the molecule interacts with the apoprotein moiety.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Azole-substituted 2-Aryl-6-methoxy-3,4-dihydronaphthalenes and -naphthalenes as Inhibitors of 17α-Hydroxylase-C17,20-Lyase (P450 17

Zhuang

Hartmann

1999

Arch. Pharm. Pharm. Med. Chem.

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The synthesis and biological evaluation of azole‐substituted 3,4‐dihydronaphthalenes (7a, 7b, 14a, 14b) and naphthalenes (12a, 12b, 16a, 16b) as nonsteroidal inhibitors of 17α‐hydroxylase‐C17,20‐lyase (P450 17, CYP 17) are described. In the case of the dihydronaphthalenes, introduction of the phenyl substituent into the 2‐position was accomplished by coupling 2‐hydroxy‐3,4‐dihydronaphthalene‐2‐trifluoromethanesulfonate 1 with the corresponding aryl‐Zn‐bromides 4a and 4b in the presence of Pd(PPh3)4 as catalyst yielding 5a and 5b as key intermediates. In the case of the naphthalenes, 2‐bromonaphthalene 9 was reacted with the corresponding Grignard reagents yielding 10a and 10b. After transformation of the intermediate acetals 5a, 5b, 10a, 10b into the corresponding aldehydes, the latter compounds were reacted with tosylmethyl isocyanide and K2CO3 to give the oxazoles 7a, 7b, 12a, and 12b. The imidazoles 14a, 14b, 16a, and 16b were prepared by heating the corresponding 4‐tosyloxazolines in ammonia, which were prepared by reacting the aldehydes with tosylmethyl isocyanide and NaCN. Using a microsomal fraction of human testicular enzyme, the title compounds did not inhibit the target enzyme.

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“…As androgens have been implicated in the development and progression of several diseases, most notably prostatic cancer, a promising alternative to treatment with antihormones and LHRH analogues might be the use of selective inhibitors of P450 17 [3,4] . Recently we have shown [3,5,6] that a dihydro-or tetrahydro-naphthalene is able to give -after linkage with an N-containing heterocycle such as imidazole, pyrazine, or pyridine -highly potent inhibitors of P450 17 (e.g., I, Chart 1 [6] ). While the heterocyclic N complexes the heme iron of P450 17, the rest of the molecule interacts with the apoprotein moiety.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Oximes of 2-Aryl-6-methoxy-3,4-dihydronaphthalene and Their Evaluation as Inhibitors of 17α-Hydroxylase-C17,20-Lyase (P450 17)

Zhuang¹,

Hartmann²

1998

Arch. Pharm. Pharm. Med. Chem.

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The synthesis and biological evaluation of oximes of 2‐aryl‐6‐methoxy‐3,4‐dihydronaphthalene (7a, 7b, 14a, 14b) as nonsteroidal inhibitors of 17α‐hydroxylase‐C17,20‐lyase (P450 17, CYP 17) is described. The target compounds were synthesized and identified by 1H NMR and MS. The preparation of the key intermediates 5a and 5b was accomplished by coupling 4a and 4b with 1 (2‐hydroxy‐6‐methoxy‐3,4‐dihydronaphthalene‐2‐trifluoromethanesulfonate) using the palladium complex Pd(PPh3)4 as catalyst. Hydrolysis of 5a and 5b in THF‐HCl solution at room temperature gave the corresponding keto compounds 6a and 6b. The other important intermediates – the substituted (E)‐2‐methylene‐1‐tetralones 10a and 10b – were obtained by condensation of 1‐tetralone with the corresponding aromatic aldehydes (9a and 9b). Hydrogenation (H2), followed by reduction (NaBH4), and subsequent hydrolysis and elimination led to the keto compounds 13a and 13b. The title compounds, the oximes 7a, 7b and 14a, 14b were formed by reaction of hydroxylamine hydrochloride with the corresponding keto compounds. Using a microsomal fraction of human testicular enzyme, 7a, 7b, 14a, and 14b inhibited the target enzyme only marginally.

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4,5‐Dihydro‐3‐(2‐pyrazinyl)naphtho[1,2‐c]pyrazole: A Potent and Selective Inhibitor of Steroid‐17α‐Hydroxylase‐C17,20‐Lyase (P450 17)

Cited by 28 publications

References 25 publications

CYP17 Inhibitors for Prostate Cancer Treatment – An Update

CYP17 Inhibitors for Prostate Cancer Treatment – An Update

Synthesis and Evaluation of Azole-substituted 2-Aryl-6-methoxy-3,4-dihydronaphthalenes and -naphthalenes as Inhibitors of 17α-Hydroxylase-C17,20-Lyase (P450 17

Synthesis of Novel Oximes of 2-Aryl-6-methoxy-3,4-dihydronaphthalene and Their Evaluation as Inhibitors of 17α-Hydroxylase-C17,20-Lyase (P450 17)

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