Pharmacological profile of MEN 11066, a novel potent and selective aromatase inhibitor.
MEN 11066 is a new non-steroidal compound which potently inhibits human placenta (K(i)=0.5 nM) and rat ovarian (K(i)=0.2 nM) aromatase in vitro. In vivo, a single oral dose of 0.3 mgkg(-1) significantly decreased uterus weight in immature rats after stimulation of uterus growth by androstenedione. MEN 11066 reduced in a dose-dependent manner plasma estradiol levels in adult female rats treated with pregnant mare serum gonadotropin (PMSG). After 2 weeks of repeated daily treatment in adult rats, a significant decrease in uterine weight was observed together with a 65% decrease in plasma estradiol, whereas plasma levels of testosterone, progesterone, aldosterone, corticosterone, cholesterol, LH and FSH were not affected. The lack of any effect by MEN 11066 on adrenal steroids was confirmed by the unchanged plasma corticosterone and aldosterone levels in immature rats and also in adult rats when the repeated treatment with MEN 11066 (15 days) was followed by the administration of a synthetic ACTH analogue. No change in 11beta-hydroxylase or 21-hydroxylase activities was produced in vitro by the addition of 10 microM MEN 11066. Fifteen-day treatment with MEN 11066 did not produce changes in several rat hepatic enzymatic activities involved in the metabolism of xenobiotics. These results demonstrated that MEN 11066 is a potent inhibitor of aromatase which does not interfere with the cytochrome P450 involved in the synthesis of other steroids or in the metabolism of xenobiotics.
Muratori
M
M
Department of Clinical Physiopathology, University of Florence, V. le Pieraccini 6, I-50139 Firenze, Italy.
Lippi
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A
Mancina
R
R
Iafrate
E M
EM
Cirillo
R
R
Lopez
G
G
Bigioni
M
M
Maggi
M
M
Criscuoli
M
M
Maggi
C A
CA
D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives / Q000494:pharmacology; D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006064:Gonadotropins, Equine / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000201:enzymology; D010920:Placenta / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013256:Steroids / Q000097:blood; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects / Q000254:growth & development
D047072:Aromatase Inhibitors; D001572:Benzofurans; D004791:Enzyme Inhibitors; D006064:Gonadotropins, Equine; C419868:MEN 11066; D013256:Steroids; D014230:Triazoles; D000735:Androstenedione; D000324:Adrenocorticotropic Hormone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001141:Aromatase