title: Exemestane (FCE 24304), a new steroidal aromatase inhibitor.
abstract: Exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione) is a novel orally active irreversible aromatase inhibitor. Its in vitro and in vivo pharmacological properties have been compared to 4-hydroxyandrostenedione (4-OHA). In preincubation studies with human placental aromatase, exemestane, like 4-OHA, showed enzyme inactivating properties with a similar affinity (Ki 26 vs 29 nM) and a lower rate of inactivation (t1/2 13.9 vs 2.1 min). Conversely, when tested in pregnant mares' serum gonadotropin-treated rats, exemestane was more potent in reducing microsomal ovarian aromatase activity than 4-OHA, after both subcutaneous (ED50 1.8 vs 3.1 mg/kg) and oral dosing (ED50 3.7 vs greater than 100 mg/kg). No interference of exemestane on desmolase or 5 alpha-reductase activity was found. The compound did not show any relevant binding affinity to steroidal receptors, but slight binding to the androgen receptor (approximately 0.2% of dihydrotestosterone), like 4-OHA. In the first phase I trial, healthy postmenopausal volunteers were given single oral doses of exemestane, ranging from 0.5 to 800 mg, and plasma [estrone (E1), estradiol (E2) and estrone sulphate (E1S)] and urinary estrogens (E1 and E2) were measured up to 5-8 days. The minimal effective dose in decreasing estrogens was 5 mg. At 25 mg the maximal suppression was observed at day 3: plasma estrogens fell to 35 (E1), 39 (E2) and 28% (E1S), and urinary estrogens fell to 20 (E1) and 25% (E2) of basal values, these effects still persisting on day 5. No effects on plasma levels of cortisol, aldosterone, 17-hydroxyprogesterone, DHEAS, LH and FSH, and no significant adverse events were observed up to the highest tested dose of 800 mg exemestane.
authors.affiliation: Oncology Line, Research and Development, Nerviano (Mi), Italy.
authors.forename: E
authors.initials: E
authors.lastname: di Salle
authors.forename: G
authors.initials: G
authors.lastname: Ornati
authors.forename: D
authors.initials: D
authors.lastname: Giudici
authors.forename: M
authors.initials: M
authors.lastname: Lassus
authors.forename: T R
authors.initials: TR
authors.lastname: Evans
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000728:Androgens / Q000494:pharmacology; D000730:Androstadienes / Q000378:metabolism / Q000494:pharmacology*; D000735:Androstenedione / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D047072:Aromatase Inhibitors; D006801:Humans; D008190:Lyases / Q000037:antagonists & inhibitors; D011987:Receptors, Steroid / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D011987:Receptors, Steroid; D000735:Androstenedione; D008190:Lyases; C056516:exemestane; C014594:formestane