Biological characterization of 10-(2-propynyl) estr-4-ene-3,17-dione (MDL 18,962), an enzyme-activated inhibitor of aromatase

doi:10.1016/0039-128X(83)90065-X

Steroids

Volume 50, Issues 1–3, July–September 1987, Pages 105-120

https://doi.org/10.1016/0039-128X(83)90065-X Get rights and content

Abstract

MDL 18,962 was shown to be a highly specific, potent (Ki = 3–4 nM), enzyme-activated inhibitor of aromatase with minimal intrinsic endocrine properties. The affinity of MDL 18,962 was higher for human and baboon placental aromatase than for rhesus placental or rodent ovarian aromatase. These species differences necessitated the development of a novel model of peripheral aromatase utilizing human enzyme. Human choriocarcinoma trophoblast xenografts in athymic nude mice were used for pharmacologic and pharmacokinetic evaluation of MDL 18,962. The ED₅₀ for inhibition of aromatase activity in these trophoblast tumors at 6 h post-treatment was 1.4 mg/kg, s.c. and 3.0 mg/kg, oral. Preliminary results indicated that the ED₅₀ for inhibition of peripheral aromatization of androgen by MDL 18,962 in female baboons was 0.01 mg/kg, i.v. and 4 mg/kg, oral.

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The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 and atamestane (SH 489) was evaluated on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumours in rats. The compounds were given subcutaneously at daily doses of 10 and 50 mg/kg for 4 weeks. Exemestane was also given orally, at daily doses of 100 and 200 mg/kg. Subcutaneous exemestane induced 30% (10 mg/kg) and 73% (50 mg/kg) regressions of established tumours and strongly reduced the appearance of new tumours. Conversely, atamestane, MDL 18962 and oral exemestane did not affect growth of established tumours nor influenced the appearance of new neoplasms. Aromatase activity of ovarian microsomes (OAA) was reduced by 85%–93% after subcutaneous exemestane and by 25%–59% after MDL 18962, and was unaffected after atamestane. Oral exemestane caused a reduction in OAA of 72%–74%. Serum luteinising hormone (LH) levels were reduced at both the subcutaneous doses of exemestane and at the higher dose of MDL 18962. Atamestane caused an increase in LH levels, while no effect was observed with oral exemestane. The LH-lowering effect of subcutaneous exemestane, the less marked effect of MDL 18962, and the ineffectiveness of oral exemestane were also observed after 10 days of treatment in ovariectomised rats. The antigonadotrophic effect of subcutaneous exemestane, which is probably due to its slight androgenic effect, could contribute to its antitumour activity in the DMBA tumour model in intact rats, through a counteraction of the negative feedback of oestrogens on gonadotropin secretion.

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Biological characterization of 10-(2-propynyl) estr-4-ene-3,17-dione (MDL 18,962), an enzyme-activated inhibitor of aromatase

Abstract

Biochem Pharmacol

J Steroid Biochem

Biochem Biophys Res Commun

Steroids

J Biol Chem

Steroids

J Biol Chem

J Steroid Biochem

Steroids

Steroids

Biochem Biophys Res Commun

J Steroid Biochem

Steroids

Biochim Biophys Acta

J Biol Chem

J Biol Chem

Ann Rep Med Chem

J Steroid Biochem

Contraception

J Biol Cheh

J Steroid Biochem

J Biol Chem

J Steroid Biochem

Suicide inhibitors as potential drugs

Clin Pharmacol Ther

Substrate-induced inactivation of aromatase by allenic and acetylenic steroids

J Am Chem Soc

Inhibition and inactivation of estrogen synthetase (aromatase) by fluorinated substrate analogs

Biochemistry

Design of mechanism-based inactivators of human placental aromatase

Cancer Res

Hydroperoxides as inactivators of aromatase: lOβ-Hydroperoxy-4-estrene-3,17-dione, crystal structure and inactivation characteristics

Biochemistry

Synthesis and evaluation of 19-aza- and 19-aminoandrostenedione analogues as potential aromatase inhibitors

J Med Chem

Synthesis of 19,19-difluoro steroids and of novel β-ring-expanded steroids

J Chem Soc Chem Commun