Preclinical pharmacological profile of nomegestrol acetate, a synthetic 19-nor-progesterone derivative

Abstract

BackgroundNomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-nor-progesterone, recently completed clinical trials for use with 17beta-estradiol in a new monophasic combined oral contraceptive. In this review, published as well as previously unpublished preclinical studies that detail the effects of NOMAC on estrogenic, progestogenic, and androgenic systems, as well as mineralocorticoid, glucocorticoid, bone, and metabolic indices are described.MethodsIn vitro assays to determine NOMAC structure-activity relationships used tissue derived from rat uteri. Transactivation profiles were performed using Chinese hamster ovary (CHO) cells transfected with cDNAs encoding human steroid receptors. Estrogenic and anti-estrogenic activities were monitored in vivo in rats as well as in vitro in human breast cancer cells. Standard in vivo techniques were used in rats to determine progestational activity; antigonadotropic, androgenic, mineralocorticoid, and glucocorticoid activities; as well as effects on bone and other metabolic indices. Ovulation inhibition was monitored in rats and primates. NOMAC’s effects on cardiovascular systems were determined in dogs and primates.ResultsNOMAC was without significant agonistic or antagonistic activity for estrogen receptor alpha or beta in vitro, and inhibited ovulation in rats and monkeys (2.5 mg/kg and 1 mg/kg, respectively). NOMAC lacked androgenic, antimineralocorticoid, glucocorticoid, and metabolic activity and exhibited moderate anti-androgenic activity in rats. NOMAC did not affect bone mineral density (BMD) in rats or hemodynamic and electrophysiologic parameters in dogs and primates.ConclusionsNOMAC is a selective progestogen structurally similar to progesterone that has modest anti-androgenic activity and does not affect lipid or carbohydrate metabolism, BMD, or many cardiovascular parameters in selected animal models.

A review of the pharmacology, clinical outcomes, and real-world effectiveness, safety, and non-contraceptive effects of NOMAC/E2

“…NOMAC is a synthetic 19-nor-progesterone derivative [9] . It is a progesterone receptor (PR) agonist that almost exclusively binds to progesterone receptors in hormone-sensitive cells derived from rats and humans [9] .…”

Breast cancer and progestins in menopausal hormone therapy: a literature review

“…NOMAC was able to inhibit estrone sulfatase and 17β-hydroxysteroid dehydrogenase activity, 2 enzymes responsible for the conversion of E1S to E2. 66 In vitro studies have shown that NOMAC blocks the conversion of estrone sulfate to estradiol in MCF-7 and T47-D hormone-dependent breast cancer cell lines. 67 According to the global proliferative measurements, NOMAC had a similar or better antiproliferative effect than LNG and DRSP.…”

Isolation, synthesis, and cytotoxicity evaluation of two impurities in nomegestrol acetate

“…It has high affinity and selectivity for human progesterone receptor (PR) and is devoid of any estrogenic, androgenic, glucocorticoid or mineralocorticoid activity. In addition, it has excellent anti‐gonadotropic activity, good progesterone receptor‐mediated anti‐estrogenic activity, and moderate anti‐androgenic activity . NOMAc has been approved and marked by commercial names such as Zoley ® , Lutenyl ® , Uniplant ® , Naemis ® , etc.…”

“…The solution was stirred at refluxing for 4 h, cooled to rt and poured onto ice-water, extracted with dichloromethane, washed with brine, dried over sodium sulfate.The solvent was removed in vacuo and the residue was purified by a silica gel column to give 7 (3.5 g, yield 67%, HPLC 98.8% at 254 nm). CDCl3 , ppm): δ 124.37, 52.34, 50.35, 48.32, 41.42, 38.31, 37.31, 36.36, 30.91, 30.31, 26.76, 25.71, 23.47, 21.26, The solution was poured into water, extracted with dichloromethane, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by a silica gel column to give impurity B (1.2 g, yield 40%, HPLC 99.73 2H), 0.74 (s, 3H); 13 C NMR (CDCl 3 , ppm): δ 203.94, 200.17, 170.69, 156.57, 139.84, 135.32, 121.47, 96.45, 62.78, 48.53, 47.52, 45.32, 41.00, 40.09, 37.40, 30.98, 30.31, 26.85, 26.45, 24.93, 23.19, 21.20, 14.20; ESI-MS: m/z 387.2146 [M+1] + ; calcd.…”