title: New non-steroidal aromatase inhibitors: focus on R76713.
abstract: R76713 is a novel triazole derivative which selectively blocks the cytochrome P450-dependent aromatase. In human placental microsomes, in FSH-stimulated rat and human granulosa cells and in human adipose stromal cells, 50% inhibition of estradiol biosynthesis was obtained at drug concentrations of 2-10 nM. In PMSG-injected female rats, R76713 lowered plasma estradiol levels by 50 and 90% 2 h after single oral doses of 0.005 and 0.05 mg/kg respectively. After 1 mg/kg, estradiol levels were suppressed by 90% for 16 h. In male cynomolgus monkeys, R76713 dose-dependently (0.03-10 micrograms/kg) inhibited peripheral aromatization with an ED50 of 0.13 microgram/kg without altering metabolic clearance rates and conversion ratios. In vitro R76713 had no effect on other P450-dependent steroidogenic enzymes up to 1000 nM at least. In rats, LHRH-, ACTH- and sodium-deprived diet stimulated plasma testosterone, corticosterone and aldosterone levels were not modified 2 h after single oral administrations of R76713 (up to 20 mg/kg). Furthermore, R76713 did not show any in vitro or in vivo estrogenic or antiestrogenic property. R76713 also induced regression of DMBA-induced mammary tumors after daily oral administration of 1 mg/kg b.i.d. In male volunteers (n = 4), a single oral dose of 5 and 10 mg lowered median plasma estradiol levels from 70 pM to the detection limit of the assay (40 pM) 4, 8 and 24 h after intake whereas no changes were detected after placebo administration. In premenopausal women (n = 15), receiving a single oral dose of 20 mg, median plasma estradiol levels decreased from 389 pM (before) to 168, 133 and 147 pM, 4, 8 and 24 h after intake whereas they remained above 420 pM after placebo (n = 7).
authors: Janssen Research Foundation, Beerse, Belgium.
authors: R
authors: R
authors: De Coster
authors: W
authors: W
authors: Wouters
authors: C R
authors: CR
authors: Bowden
authors: H
authors: H
authors: Vanden Bossche
authors: J
authors: J
authors: Bruynseels
authors: R W
authors: RW
authors: Tuman
authors: R
authors: R
authors: Van Ginckel
authors: E
authors: E
authors: Snoeck
authors: A
authors: A
authors: Van Peer
authors: P A
authors: PA
authors: Janssen
mesh_terms: D000818:Animals; D047072:Aromatase Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D011247:Pregnancy; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D014230:Triazoles; C060523:vorozole