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

BACKGROUND: Nomegestrol 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 In this review, published as well as previously unpublished preclinical studies that detail the effects of NOMAC on estrogenic, progestogenic, and androgenic systems, as well as mineralocorticoid, glucocorticoid, bone,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. METHODS: In 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. RESULTS: NOMAC 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. CONCLUSIONS: NOMAC 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.

Non-invasive translational Cynomolgus model for studying folliculogenesis and ovulation using color Doppler ultrasonography.

BACKGROUND: In women, different events of folliculogenesis can be measured and evaluated using ultrasound (US) technology. The availability of a non-invasive translational non-human primate model to study these processes would represent a major contribution to further advance R&D efforts toward novel therapies in assisted reproduction. METHODS: In our study, follicular growth and ovulation was measured in six cyclic Cynomolgus monkeys using abdominal Doppler US. RESULTS: The mean follicular diameter on cycle day -6 (cycle day 0=day of ovulation) was 3.7mm that increased to 6.8mm on cycle day -1. After ovulation, the mean diameter decreased to 4.6mm, confirming ovulation. The mean percentage of follicular size reduction after ovulation was 31%. CONCLUSION: Ultrasonography in combination with color-flow Doppler imaging was shown to be a useful, non-invasive translational method to measure ovarian follicular growth and occurrence and timing of follicular rupture in Cynomolgus monkeys.

A small-molecule fusion inhibitor of influenza virus is orally active in mice.

Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.

Nomegestrol acetate: steroid receptor transactivation profile in Chinese hamster ovary cells and ovulation inhibition in rat and monkey.

BACKGROUND: Activity of nomegestrol acetate (NOMAC), levonorgestrel (LNG), drospirenone (DRSP), dienogest (DNG) and progesterone on human steroid receptor transactivation was investigated. Ovulation inhibition by NOMAC, LNG and progesterone was tested. STUDY DESIGN: The progestogen receptor profile was determined in Chinese hamster ovary cells transfected with human progesterone B (PRB), androgen, estrogen (ER(α) and ER(ß)), glucocorticoid (GR) and mineralocorticoid (MR) receptors, respectively. Ovulation inhibition was tested in rats and monkeys. RESULTS: Agonistic potency rankings for PRB were LNG=NOMAC≫progesterone≫DRSP>DNG. No antagonistic activity at PRB was observed. Only LNG had androgenic activity. Antiandrogenic potency rankings were LNG≫NOMAC>progesterone>DNG>DRSP. All agents were devoid of activity at ER(α), ER(ß) and GR. Only progesterone, DRSP and LNG had anti-MR activity. The NOMAC dose inhibiting ovulation at 50% ranged from 0.14 mg/kg (monkey) to 1.25 to 5.0 mg/kg (rat). CONCLUSION: Nomegestrol acetate is a selective progestogen and a potent inhibitor of ovulation in the rat and monkey.